Therapeutic agents - I

ABSTRACT

The present invention relates generally to chemical agents useful in the treatment and prophylaxis of infection by pathogenic or potentially pathogenic entities, or entities capable of opportunistic infection in mammals, including humans and primates, non-mammalian animals and avian species. More particularly, the present invention provides a chemical agent of the macrocyclic diterpene family obtainable from a member of the Euphorbiaceae family of plants or botanical or horticultural relatives thereof or derivatives or chemical analogues or chemically synthetic forms of the agents for use in the treatment or prophylaxis of infection by pathogenic entities in mammalian, animal and avian subjects. The present invention further contemplates a method for the prophylaxis and/or treatment in mammalian, animal or avian subjects of infection or potential infection by pathogenic entities by the topical or systemic administration of a macrocyclic diterpene obtainable from a member of the Euphorbiaceae family of plants or their botanical or horticultural derivatives or a derivative, chemical analogue or chemically synthetic form of the agent. The chemical agent of the present invention may be in the form of a purified compound, mixture of compounds, a precursor form of one or more of the compounds capable of chemical transformation into a therapeutically active agent or in the form of a chemical fraction, sub-fraction, preparation or extract of the plant.

FIELD OF THE INVENTION

[0001] The present invention relates generally to chemical agents usefulin the treatment and prophylaxis of infection by pathogenic orpotentially pathogenic entities, or entities capable of opportunisticinfection in mammals, including humans and primates, non-mammaliananimals and avian species. More particularly, the present inventionprovides a chemical agent of the macrocyclic diterpene family obtainablefrom a member of the Euphorbiaceae family of plants or botanical orhorticultural relatives thereof or derivatives or chemical analogues orchemically synthetic forms of the agents for use in the treatment orprophylaxis of infection by pathogenic entities in mammalian, animal andavian subjects. The present invention further contemplates a method forthe prophylaxis and/or treatment in mammalian, animal or avian subjectsof infection or potential infection by pathogenic entities by thetopical or systemic administration of a macrocyclic diterpene obtainablefrom a member of the Euphorbiaceae family of plants or their botanicalor horticultural derivatives or a derivative, chemical analogue orchemically synthetic form of the agent. The chemical agent of thepresent invention may be in the form of a purified compound, mixture ofcompounds, a precursor form of one or more of the compounds capable ofchemical transformation into a therapeutically active agent or in theform of a chemical fraction, sub-fraction, preparation or extract of theplant.

BACKGROUND OF THE INVENTION

[0002] Bibliographic details of the publications referred to by authorin this specification are collected at the end of the description.

[0003] Reference to any prior art in this specification is not, andshould not be taken as, an acknowledgment or any form of suggestion thatthis prior art forms part of the common general knowledge in Australiaor any other country.

[0004] Natural product screening is a term applied to the screening ofnatural environments for bioactive molecules. Particularly sought afterbioactive molecules are those having potential as useful therapeuticagents. Natural environments include plants, microorganisms, coral andmarine animals. The search for potential therapeutic agents for thetreatment of cancer and infection by pathogenic organisms remains animportant focus.

[0005] The Euphorbiaceae family of plants covers a wide variety ofplants including weeds of Euphorbia species. There have been a varietyof inconclusive reports on the potential effects of the sap of theseplants on a variety of conditions as well as promoting tumorigenesis andcausing skin and ocular irritation.

[0006] The most intensively studied species of this group is Euphorbiapilulifera L (synonyms E. hirta L., E. capitata Lam.), whose commonnames include pill-bearing spurge, snakeweed, cat's hair, Queenslandasthma weed and flowery-headed spurge. The plant is widely distributedin tropical countries, including India, and in Northern Australia,including Queensland.

[0007] A recent report describes selective cytotoxicity of a number oftiglilane diterpene esters from the latex of Euphorbia poisonii, ahighly toxic plant found in Northern Nigeria, which is used as a gardenpesticide. One of these compounds has a selective cytotoxicity for thehuman kidney carcinoma cell line A-498 more than 10,000 times greaterthan that of adriamycin (Fatope et al., 1996).

[0008]Euphorbia hirta plants and extracts thereof have been consideredfor a variety of purposes, including tumor therapy (EP 0 330 094),AIDS-related complex and AIDS (HU-208790) and increasing immunity and asan anti-fungoid agent for treatment of open wounds (DE-4102054).

[0009] Thus, while there are isolated reports of anti-cancer activity ofvarious Euphorbia preparations (see Fatope et al., 1996; Oksuz et al.,1996), not only are the compounds present in at least one Euphorbiaspecies reported to be carcinogenic (Evans and Osman, 1974; Stavric andStolz, 1976; Hecker, 1970), but at least one species has a skin-irritantand tumor-promoting effect (Gundidz et al., 1993) and another speciesreduces EBV-specific cellular immunity in Burkitt's lymphoma (Imai,1994).

[0010] In accordance with the present invention, the inventors haveidentified chemical agents and fractions comprising these agents whichare useful in the treatment and prophylaxis of

SUMMARY OF THE INVENTION

[0011] Throughout this specification, unless the context requiresotherwise, the word “comprise”, or variations such as “comprises” or“comprising”, will be understood to imply the inclusion of a statedelement or integer or group of elements or integers but not theexclusion of any other element or integer or group of elements orintegers.

[0012] The present invention is predicated in part on the identificationof chemical agents and fractions comprising same from plants of theEuphorbiaceac family which are useful in the treatment and prophylaxisof infection by pathogenic, potentially pathogenic and opportunisticorganisms. Such organisms include prokaryotes, eukaryotes and viruses.The inventors have further identified that the chemical agents of thepresent invention are capable of modulating protein kinase C (PKC)activity thus providing a basis for the treatment of conditions wherePKC activity is required to be up-regulated or down-regulated.

[0013] Accordingly, one aspect of the present invention contemplates amethod for the treatment or prophylaxis of a condition associated withthe presence of a biological entity or part thereof or a toxin or venomtherefrom or a genetic event caused thereby in a subject, said methodcomprising the administration to said subject of a symptom-amelioratingeffective amount of a chemical agent obtainable from a plant of theEuphorbiaceae family or a derivative or chemical analogue thereof whichchemical agent is a macrocyclic diterpene selected from compounds of theingenane, pepluane and jatrophane families and which chemical agent orderivative or chemical analogue as represented by any one of the generalformulae (I)-(V) as defined herein and which chemical agent orderivative or chemical analogue thereof is capable of modulating PKCactivity, PKC-dependent gene expression or PKC enzyme turnover andwherein said chemical agent or its derivatives or chemical analogues isadministered for a time and under conditions sufficient to ameliorateone or more symptoms associated with said biological entity.

[0014] Yet another aspect of the present invention contemplates a methodfor the treatment or prophylaxis of a microbial infection in a subject,said method comprising the administration to said subject of asymptom-ameliorating effective amount of a macrocyclic diterpene, or achemical fraction comprising same from a plant of the familyEuphorbiaceae or a derivative or chemical analogue of said macrocyclicditerpene having the structures as defined above wherein saidmacrocyclic diterpene or its derivative or chemical analogue modulatesPKC activity, synthesis or enzyme turnover, said administration beingfor a time and under conditions sufficient to ameliorate one or moresymptoms of the infection.

[0015] Still another aspect of the present invention provides a methodfor the treatment or prophylaxis of an infection by a lower eukaryoticorganism in a subject, said method comprising the administration to saidsubject of a symptom-ameliorating effective amount of a macrocyclicditerpene or chemical fraction comprising same from a plant of thefamily Euphorbiaceae or a derivative or chemical analogue of saidmacrocyclic diterpene having the structures as defined above whereinsaid macrocyclic diterpene or its derivative or chemical analoguemodulates PKC activity, synthesis or enzyme turnover, saidadministration being for a time and under conditions sufficient toameliorate one or more symptoms of the infection.

[0016] Still yet another aspect of the present invention provide amethod for the treatment or prophylaxis of an infection by a complexeukaryotic organism in a subject, said method comprising theadministration to said subject of a symptom-ameliorating effectiveamount of a macrocyclic diterpene, or a chemical fraction comprisingsame from a plant of the family Euphorbiaceae or a derivative orchemical analogue of said macrocyclic diterpene having the structures asdefined above wherein said macrocyclic diterpene or its derivative orchemical analogue modulates PKC activity, synthesis or enzyme turnover,said administration being for a time and under conditions sufficient toameliorate one or more symptoms of the infection.

[0017] Even yet another aspect of the present invention provide a methodfor the treatment or prophylaxis of an infection by a virus in asubject, said method comprising the administration to said subject of asymptom-ameliorating effective amount of a macrocyclic diterpene, or achemical fraction comprising same from a plant of the familyEuphorbiaceae or a derivative or chemical analogue of said macrocyclicditerpene having the structures as defined above wherein saidmacrocyclic diterpene or its derivative or chemical analogue modulatesPKC activity, synthesis or enzyme turnover, said administration beingfor a time and under conditions sufficient to ameliorate one or moresymptoms of the infection.

[0018] A further aspect of the present invention contemplates a methodof assessing the suitability of a chemical agent from Euphorbiaceae forthe practice of the present invention. Numerical values are assigned tochemical agents including fractions comprising the chemical agents asset forth, for example, in Table A: TABLE A Feature Value An ability tomodulate PKC activity or effect +1 An ability to induce bipolardendritic activity +1 An ability to displace phorbol dibutyrate from +1binding to PKC An ability to induce respiratory burst in leucocytes +1An ability to stimulate phagocytosis in peripheral +1 blood mononuclearcells An ability to be derived from a member of the +1 Euphorbiaceaefamily. Derived from E. peplus +3 Water extractible from the sap ofEuphorbia sp. +2 An ability to activate latent virus in vitro +4 A lowertumor promotion activity than TPA/PMA +2

[0019] Another aspect of the present invention contemplates a method forthe treatment or prophylaxis of infection or colonization or presence ofa biological entity in a subject, said method comprising administrationto said subject of a symptom-ameliorating effective amount of amacrocyclic diterpene obtainable from a Euphorbiaceae plant or itsbotanical or horticultural relative, said macrocyclic diterpene beingselected from an ingenane, pepluane or jatrophane, or a derivative orchemical analogue thereof, having the structure represented by any oneof the general formulae (I)-(V) as defined below and wherein saidchemical agent exhibits a potency of agent (P_(A)) of >10, wherein theP_(A)=ΣI_(V) where I_(V) is a numerical value associated with aparticular feature as defined in Table A or pharmaceutically acceptablesalts of these, said chemical agent being administered for a time andunder conditions sufficient to ameliorate at least one symptom caused byor associated with the biological entity.

[0020] Yet another aspect of the present invention contemplates acomputer program product for assessing the likely usefulness of acandidate compound or group of compounds for treating or preventinginfection or colonization or presence of a biological entity in asubject, said product comprising:

[0021] (1) code that receives as input index values for at least twofeatures associated with said compound(s), wherein said features areselected from:

[0022] (a) the ability to modulate PKC activity or effect;

[0023] (b) the ability to induce bipolar dendritic activity;

[0024] (c) the ability to be derived from a member of the Euphorbiaceaefamily;

[0025] (d) the ability to be derived from E. peplus;

[0026] (e) the ability to be water extractable from the sap of aEuphorbia species; or

[0027] (f) the ability to activate latent virus;

[0028] (g) less tumor promoting capacity than TPA or PMA;

[0029] (2) code that adds said index values to provide a sumcorresponding to a potency value for said compound(s); and

[0030] (3) a computer readable medium that stores the codes.

[0031] Still another aspect of the present invention extends to acomputer for assessing the likely usefulness of a candidate compound orgroup of compounds for treating or preventing infection or colonizationor presence of a biological entity in a subject, wherein said computercomprises:

[0032] (1) a machine-readable data storage medium comprising a datastorage material encoded with machine-readable data, wherein saidmachine-readable data comprise index values for at least two featuresassociated with said compound(s), wherein said features are selectedfrom:

[0033] (a) the ability to modulate PKC activity or effect;

[0034] (b) the ability to induce bipolar dendritic activity;

[0035] (c) the ability to be derived from a member of the Euphorbiaceacfamily;

[0036] (d) the ability to be derived from E. peplus;

[0037] (e) the ability to be water extractable from the sap of aEuphorbia species; or

[0038] (f) the ability to activate latent virus;

[0039] (g) less tumor promoting capacity than TPA or PMA;

[0040] (2) a working memory for storing instructions for processing saidmachine-readable data;

[0041] (3) a central-processing unit coupled to said working memory andto said machine-readable data storage medium, for processing saidmachine readable data to provide a sum of said index valuescorresponding to a potency value for said compound(s); and

[0042] (4) an output hardware coupled to said central processing unit,for receiving said potency value.

BRIEF DESCRIPTION OF THE FIGURES

[0043]FIG. 1 shows the activation of PKC, using a fluorescent peptideassay (“PepTag” non-radioactive protein kinase kit, Promega). Lane 1,PKC and substrate alone; lane 2, plus positive control activator; lane3, plus 100 ng/ml TPA; lane 4, plus 0.1 ng/ml TPA; lane 5, plus 0.01ng/ml TPA; lane 6, plus 0.001 ng/ml TPA; lane 7, ether extract of E.peplus sap in DEM, diluted 1 in 5; lane 8, aqueous layer from etherextraction, diluted {fraction (1/25)}; lane 9, crude sap diluted{fraction (1/25)}; lane 10, DME alone.

[0044]FIG. 2 shows the activation of PKC by E. peplus fractions. Lanes 1and 2, same as FIG. 1; lane 3, 2 mg/ml fraction H; lane 4, 2 mg/mlingenanes.

[0045]FIG. 3 is photographic representation showing the results of a PKCassay using rat brain PKC. Lane 1, negative control; lane 2, positivecontrol; lane 3, empty; lane 4, PEP001 ({fraction (1/125)} dilution),lane 5, PEP001 ({fraction (1/500)} dilution) and lane 6, TPA (20 μg).

[0046]FIG. 4 is a photographic representation showing the activation ofPKC in MM96L cells expressing PKC fused to green fluorescent protein(GFP). (A) PKCβ expressed in the nuclei of MM96L human melanoma PKCMM96L cells in the absence of drug. (B) After treatment with crude E.peplus extract for 2 hr.

[0047]FIG. 5 is a photographic representation showing induction oftranslocation of activated PKCs by the compounds of the instantinvention to the cytoplasm, plasma membrane and to the Golgi orsimilarly located cellular structure.

[0048]FIG. 6 is a graphical representation showing the induction oftranslation of the classical and novel PKC isoforms in response toPEP003, PEP005, bryostatin-1 and TPA.

[0049]FIG. 7 is a graphical representation showing the activation of HIVfrom U1 cells.

[0050]FIG. 8 is a graphical representation showing treatment of lyticHIV infection of peripheral blood mononuclear cells (PBMC) with PEP003,PEP004, TPA and ingenol, expressed as p24 production over a 10 daytreatment period. (A) Uninfected cells, (B) low titer infected cells,(C) low titer infected cells represented as p24 production versus drugconcentration, (D) same as (C) but high titer infection.

[0051]FIG. 9 is a photographic representation showing the recruitment ofneutrophils in the skin induced by PEP001 extract. (A) Normal skin ofnude mouse. (B) Skin of nude mouse showing infiltration of neutrophilsone day after treatment with E. peplus sap.

[0052]FIG. 10 is a photographic representation showing effect of PEP010onrecruitment of neutrophils in normal skin of nude mouse and skinoverlying subcutaneously implanted B16 melanoma. (A) 24 hr treatment,(B) 48 hr treatment.

[0053]FIG. 11 is a graphical representation illustrating the ability ofPEP001 to induce the release of superoxide radical, as demonstrated byfluorescence-activated cell sorting.

[0054]FIG. 12 is a graphical representation showing the effect ofpre-treatment of leukocytes with PEP003 on E. coli activity (16 hrincubation), relative to PBS control; depicted as numbers of E. colicells/ml media.

[0055]FIG. 13 is a graphical representation showing the effect ofpre-treatment of leukocytes with PEP003 on E. coli numbers depicted interms of turbidity.

[0056]FIG. 14 is a photographic representation showing production ofviral capsid antigen (VCA) in B95-8 (EBV+ Marmoset cell line) aftertreatment with TPA, PEP003 and PEP004 for 3 and 7 days.

[0057]FIG. 15 is a photographic representation showing production ofviral capsid antigen (VCA) in BL74 and Mutu I (Burkitts lymphoma celllines) after treatment with TPA, PEP003 and PEP004 for 3 and 7 days.

[0058]FIG. 16 is a photographic representation showing production ofBZLF1 (the initial transactivator of EBV) after treatment with TPA,PEP003 and PEP004 for 3 and 7 days.

[0059]FIG. 17 is a graphical representation showing activation ofnatural killer cell activity, assayed as % specific lysis of K562 cells(a natural killer—sensitive cell line) after pre-treatment of AO2-Mmelanoma cells with PEP003 and TPA.

[0060]FIG. 18 is a graphical representation showing survival of Jamcells after treatment with saps from the Euphorbiaceae, expressed aspercentage cell survival determined by sulfurhodamine B staining ofcells.

[0061]FIG. 19 is a diagrammatic representation of a system used to carryout the instructions encoded by the storage medium of FIGS. 9 and 10.

[0062]FIG. 20 is a diagrammatic representation of a cross-section of amagnetic storage medium.

[0063]FIG. 21 is a diagrammatic representation of a cross-section of anoptically readable data storage system.

[0064] Compounds may be referred to in the subject specification by acompound code. These are defined as below: TABLE OF COMPOUND CODESCOMPOUND CODE DESCRIPTION PEP001 Crude sap PEP002 Methanol and etherextract of E. peplus sap prepared according to Example 7 ofPCT/AU98/00656 PEP003 Ingenane enriched fraction prepared according toExamples 21 and 23 PEP004 Jatrophane/Pepluane enriched fraction preparedaccording to Example 7 of PCT/AU98/00656 PEP00520-hydroxy-ingenol-3-angelate PEP006 Ingenol-3-angelate PEP00820-O-acetyl-ingenol-3-angelate PEP009 Acetone Extract of XAD preparedaccording to Example 21 PEP010 Ingenane enriched fraction preparedaccording to Examples 22 and 23

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0065] The present invention is predicated in part on the identificationof biologically useful properties of chemical agents and chemicalfractions comprising these agents obtainable from a member of theEuphorbiaceae family of plants or their botanical or horticulturalrelatives. These biologically useful properties include their use in theprophylaxis and/or treatment of infection, colonization or presence of aparticular pathological entity or potential pathological entity or anentity capable of opportunistic infection or colonization in aparticular subject as well as the amelioration of symptoms associatedwith or produced from such an entity.

[0066] The term “treatment” is used in its broadest sense and includesthe prevention of infection or growth of an entity to pathologicallevels, the inhibition in growth or reduction in levels of an entityfrom pathological levels to asymptomatic levels or to levels in betweenas well as facilitating the amelioration of the effects of symptoms ofinfection, colonization or presence of an entity.

[0067] The term “prophylaxis” is also used herein in its broadest senseto encompass a reduction in the risk of development of infection,colonization or presence of an entity to pathological levels. In certainconditions, an agent may act to treat a subject prophylactically.Furthermore, the prophylactic administration of an agent may result inthe agent becoming involved in the treatment of a pathologicalcondition. Use of the terms “treatment” or “prophylaxis” is not to betaken as limiting the intended result which is to reduce the incidenceof infection, colonization or presence of a pathological entity, apotentially pathogenic entity or an entity capable of opportunisticinfection, colonization or presence or to reduce the effects and/or toameliorate the symptoms or risk of development of symptoms caused orfacilitated by the infection, colonization or presence of the entity.

[0068] Furthermore, the symptoms of a pathological condition induced orfacilitated by the infection, colonization or presence of a particularentity may be due to the entity itself or to a toxin,membrane-associated moiety, a soluble or releasable moiety, venom orother molecule associated with the entity. The treatment and prophylaxisof the condition extends, therefore, to the treatment or prophylaxis ofsuch extraneous factors which may persist after the entity has beenremoved or lowered to non-pathological-causing levels.

[0069] The present invention is particularly directed to the use of oneor more macrocyclic diterpenes from a member of the Euphorbiaceae familyof plants or botanical or horticultural relatives of such plants.Reference herein to a member of the Euphorbiaceae family includesreference to species from the genera Acalypha, Acidoton, Actinostemon,Adelia, Adenocline, Adenocrepis, Adenophaedra, Adisca, Agrostistachys,Alchornea, Alchorneopsis, Alcinaeanthus, Alcoceria, Aleurites, Amanoa,Andrachne, Angostyles, Anisophyllum, Antidesma, Aphora, Aporosa,Aporosella, Argythamnia, Astrococcus, Astrogyne, Baccanrea,Baliospermum, Bernardia, Beyeriopsis, Bischofia, Blachia, Blumeodondron,Bonania, Bradleia, Breynia, Breyniopsis, Briedelia, Buraeavia,Caperonia, Caryodendron, Celianella, Cephalocroton, Chaenotheca,Chaetocarpus, Chamaesyce, Cheilosa, Chiropetalum, Choriophyllum, Cicca,Chaoxylon, Cleidon, Cleistanthus, Cluytia, Cnesmone, Cnidoscolus,Coccoceras, Codiaeum, Coelodiscus, Conami, Conceveiba, Conceveibastrum,Conceveibum, Corythea, Croizatia, Croton, Crotonopsis, Crozophora,Cubanthus, Cunuria, Dactylostemon, Dalechampia, Dendrocousinsia,Diaspersus, Didymocistus, Dimorphocalyx, Discocarpus, Ditaxis,Dodecastingma, Drypetes, Dysopsis, Elateriospermum, Endadenium,Endospermum, Erismanthus, Erythrocarpus, Erythrochilus, Eumecanthus,Euphorbia, Euphorbiodendron, Excoecaria, Flueggea, Calearia, Garcia,Gavarretia, Gelonium, Giara, Givotia, Glochidion, Clochidionopsis,Glycydendron, Gymnanthes, Gymnosparia, Haematospermum, Hendecandra,Hevea, Hieronima, Hieronyma, Hippocrepandra, Homalanthus, Hymenocardia,Janipha, Jatropha, Julocroton, Lasiocroton, Leiocarpus, Leonardia,Lepidanthus, Leucocroton, Mabea, Macaranga, Mallotus, Manihot, Mappa,Maprounea, Melanthesa, Mercurialis, Mettenia, Micrandra, Microdesmis,Microelus, Microstachy, Maocroton, Monadenium, Mozinna, Neoscortechinia,Omalanthus, Omphalea, Ophellantha, Orbicularia, Ostodes, Oxydectes,Palenga, Pantadenia, Paradrypeptes, Pausandra, Pedilanthus, Pera,Peridium, Petalostigma, Phyllanthus, Picrodendro, Pierardia,Pilinophytum, Pimeleodendron, Piranhea, Platygyna, Plukenetia,Podocalyx, Poinsettia, Poraresia, Prosartema, Pseudanthus, Pycnocoma,Quadrasia, Reverchonia, Richeria, Richeriella, Ricinella, Ricinocarpus,Rottlera, Sagotia, Sanwithia, Sapium, Savia, Sclerocroton, Sebastiana,Securinega, Senefeldera, Senefilderopsis, Serophyton, Siphonia,Spathiostemon, Spixia, Stillingia, Strophioblachia, Synadenium,Tetracoccus, Tetraplandra, Tetrorchidium, Thyrsanthera, Tithymalus,Trageia, Trewia, Trigonostemon, Tyria and Xylophylla.

[0070] The most preferred genus and most suitable for the practice ofthe present invention is the genus Euphorbia. Particularly usefulspecies of this genus include Euphorbia aaron-rossii, Euphorbiaabbreviata, Euphorbia acuta, Euphorbia alatocaulis, Euphorbiaalbicaulis, Euphorbia algomarginata, Euphorbia aliceae, Euphorbia alta,Euphorbia anacampseros, Euphorbia andromedae, Euphorbia angusta,Euphorbia anthonyi, Euphorbia antiguensis, Euphorbia apocynifolia,Euphorbia arabica, Euphorbia ariensis, Euphorbia arizonica, Euphorbiaarkansana, Euphorbia arteagae, Euphorbia arundelana, Euphorbiaastroites, Euphorbia atrococca, Euphorbia baselicis, Euphorbiabatabanensis, Euphorbia bergeri, Euphorbia bermudiana, Euphorbiabicolor, Euphorbia biformis, Euphorbia bifurcata, Euphorbia bilobata,Euphorbia biramensis, Euphorbia biuncialis, Euphorbia blepharostipula,Euphorbia blodgetti, Euphorbia boerhaavioides, Euphorbia boliviana,Euphorbia bracei, Euphorbia brachiata, Euphorbia brachycera, Euphorbiabrandegee, Euphorbia brittonii, Euphorbia caesia, Euphorbia calcicola,Euphorbia campestris, Euphorbia candelabrum, Euphorbia capitellata,Euphorbia carmenensis, Euphorbia carunculata, Euphorbia cayensis,Euphorbia celastroides, Euphorbia chalicophila, Euphorbia chamaerrhodos,Euphorbia chamaesula, Euphorbia chiapensis, Euphorbia chiogenoides,Euphorbia cinerascens, Euphorbia clarionensis, Euphorbia colimae,Euphorbia colorata, Euphorbia commutata, Euphorbia consoquitlae,Euphorbia convolvuloides, Euphorbia corallifera, Euphorbia creberrima,Euphorbia crenulata, Euphorbia cubensis, Euphorbia cuspidata, Euphorbiacymbiformis, Euphorbia darlingtonii, Euphorbia defoliata, Euphorbiadegeneri, Euphorbia deltoidea, Euphorbia dentata, Euphorbia depressaEuphorbia dictyosperma, Euphorbia dictyosperma, Euphorbia dioeca,Euphorbia discoidalis, Euphorbia dorsiventralis, Euphorbia drumondii,Euphorbia duclouxii, Euphorbia dussii, Euphorbia eanophylla, Euphorbiaeggersii, Euphorbia eglandulosa, Euphorbia elata, Euphorbia enalla,Euphorbia eriogonoides, Euphorbia eriophylla, Euphorbia esculaeformis,Euphorbia espirituensis, Euphorbia esula, Euphorbia excisa, Euphorbiaexclusa, Euphorbia exstipitata, Euphorbia exstipulata, Euphorbiafendleri, Euphorbia filicaulis, Euphorbia filiformis, Euphorbia florida,Euphorbia fruticulosa, Euphorbia garber, Euphorbia gaumerii, Euphorbiagerardiana, Euphorbia geyeri, Euphorbia glyptosperma, Euphorbiagorgonis, Euphorbia gracilior, Euphorbia gracillima, Euphorbia gradyi,Euphorbia graminea, Euphorbia graminiea Euphorbia grisea, Euphorbiaguadalajarana, Euphorbia guanarensis, Euphorbia gymnadenia, Euphorbiahaematantha, Euphorbia hedyotoides, Euphorbia heldrichii, Euphorbiahelenae, Euphorbia helleri, Euphorbia helwigii, Euphorbia henricksonii,Euphorbia heterophylla, Euphorbia hexagona, Euphorbia hexagonoides,Euphorbia hinkleyorum, Euphorbia hintonii, Euphorbia hirtula, Euphorbiahirta, Euphorbia hooveri, Euphorbia humistrata, Euphorbia hypericifolia,Euphorbia inundata, Euphorbia involuta, Euphorbia jaliscensis, Euphorbiajejuna, Euphorbia johnston, Euphorbia juttae, Euphorbia knuthii,Euphorbia lasiocarpa, Euphorbia lata, Euphorbia latazi, Euphorbialatericolor, Euphorbia laxiflora Euphorbia lecheoides, Euiphorbialedienii, Euphorbia leucophylla, Euphorbia lineata, Euphorbialinguiformis, Euphorbia longecornuta, Euphorbia longepetiolata,Euphorbia longeramosa, Euphorbia longinsulicola, Euphorbia longipila,Euphorbia lupulina, Euphorbia lurida, Euphorbia lycioides, Euphorbiamacropodoides, macvaughiana, Euphorbia manca, Euphorbia mandoniana,Euphorbia mangleti, Euphorbia mango, Euphorbia marylandica, Euphorbiamayana, Euphorbia melanadenia, Euphorbia melanocarpa, Euphorbiameridensis, Euphorbia mertonii, Euphorbia mexiae, Euphorbiamicrocephala, Euphorbia microclada, Euphorbia micromera, Euphorbiamisella, Euphorbia missurica, Euphorbia montana, Euphorbia montereyana,Euphorbia multicaulis, Euphorbia multiformis, Euphorbia multinodis,Euphorbia multiseta, Euphorbia muscicola, Euphorbia neomexicana,Euphorbia nephradenia, Euphorbia niqueroana, Euphorbia oaxacana,Euphorbia occidentalis, Euphorbia odontodenia, Euphorbia olivacea,Euphorbia olowaluana, Euphorbia opthalmica, Euphorbia ovata, Euphorbiapachypoda, Euphorbia pachyrhiza, Euphorbia padifolia, Euphorbia palmeri,Euphorbia paludicola, Euphorbia parciflora, Euphorbia parishii,Euphorbia parryi, Euphorbia paxiana, Euphorbia pediculifera, Euphorbiapeplidion, Euphorbia peploides, Euphorbia peplus, Euphorbia pergamena,Euphorbia perlignea, Euphorbia petaloidea, Euphorbia petaloidea,Euphorbia petrina, Euphorbia picachensis, Euphorbia pilosula, Euphorbiapilulifera, Euphorbia pinariona, Euphorbia pinetorum, Euphorbiapionosperma, Euphorbia platysperma, Euphorbia plicata, Euphorbiapoeppigii, Euphorbia poliosperma, Euphorbia polycarpa, Euphorbiapolycnemoides, Euphorbia polyphylla, Euphorbia portoricensis, Euphorbiaportulacoides Euphorbia portulana, Euphorbia preslii, Euphorbiaprostrata, Eulphorbia pteroneura, Euphorbia pycnanthema, Euphorbiaramosa, Euphorbia rapulum, Euphorbia remyi, Euphorbia retroscabra,Euphorbia revoluta, Euphorbia rivularis, Euphorbia robusta, Euphorbiaromosa, Euphorbia rubida, Euphorbia rubrosperma, Euphorbia rupicola,Euphorbia sanmartensis, Euphorbia saxatilis M. Bieb, Euphorbiaschizoloba, Euphorbia sclerocyathium, Euphorbia scopulorum, Euphorbiasenilis, Euphorbia serpyllifolia, Euphorbia serrula, Euphorbia setilobaEngelm, Euphorbia sonorae, Euphorbia soobyi, Euphorbia sparsiflora,Euphorbia sphaerosperma, Euphorbia syphilitica, Euphorbia spruceana,Euphorbia subcoerulea, Euphorbia stellata, Euphorbia submammilaris,Euphorbia subpeltata, Euphorbia subpubens, Euphorbia subreniforme,Euphorbia subtrifoliata, Euphorbia succedanea, Euphorbia tamaulipasana,Euphorbia telephioides, Euphorbia tenuissima, Euphorbia tetrapora,Euphorbia tirucalli, Euphorbia tomentella, Euphorbia tomentosa,Euphorbia torralbasii, Euphorbia tovariensis, Euphorbia trachysperma,Euphorbia tricolor, Euphorbia troyana, Euphorbia tuerckheimii, Euphorbiaturczaminowii, Euphorbia umbellulata, Euphorbia undulata, Euphorbiavermiformis, Euphorbia versicolor, Euphorbia villifera, Euphorbiaviolacea, Euphorbia whitei, Euphorbia xanti Engelm, Euphorbia xylopodaGreemn., Euphorbia yayalesia Urb., Euphorbia yungasensis, Euphorbiazeravschanica and Euphorbia zinniiflora.

[0071] Particularly preferred species of the genus Synadenium includeSynadenium grantii and Synadenium compactum.

[0072] Particularly preferred species of the genus Monadenium includeMonadenium lugardae and Monadenium guentheri.

[0073] A preferred species of the genus Endadenium is Endadeniumgossweileni.

[0074]Euphorbia peplus is particularly useful in the practice of thepresent invention. Reference herein to “Euphorbia peplus” or itsabbreviation “E. peplus” includes various varieties, strains, lines,hybrids or derivatives of this plant as well as its botanical orhorticultural relatives. Furthermore, the present invention may bepracticed using a whole Euphorbiaceae plant or parts thereof includingsap or seeds or other reproductive material may be used. Generally, forseeds or reproductive material to be used, a plant or plantlet is firstrequired to be propagated.

[0075] Reference herein to a Euphorbiaceae plant, a Euphorbia species orE. peplus further encompasses genetically modified plants. Geneticallymodified plants include trangenic plants or plants in which a trait hasbeen removed or where an endogenous gene sequence has beendown-regulated, mutated or otherwise altered including the alteration orintroduction of genetic material which exhibits a regulatory effect on aparticular gene. Consequently, a plant which exhibits a character notnaturally present in a Euphorbiaceae plant or a species of Euphorbia orin E. peplus is nevertheless encompassed by the present invention and isincluded within the scope of the above-mentioned terms.

[0076] The macrocyclic diterpenes are generally in extracts of theEuphorbiaceae plants. An extract may comprise, therefore, sap or liquidor semi-liquid material exuded from, or present in, leaves, stem,flowers, seeds, bark or between the bark and the stem. Most preferably,the extract is from sap. Furthermore, the extract may comprise liquid orsemi-liquid material located in fractions extracted from sap, leaves,stems, flowers, bark or other plant material of the Euphoriaceae plant.For example, plant material may be subject to physical manipulation todisrupt plant fibres and extracellular matrix material and inter- andintra-tissue extracted into a solvent including an aqueous environment.All such sources of the macrocyclic diterpenes are encompassed by thepresent invention including macrocyclic diterpenes obtained by syntheticroutes.

[0077] The preferred macrocyclic diterpenes are selected from compoundsof the ingenane, pepluane and jatrophane families. A compound is statedto be a member of the ingenane, pepulane or jatrophane families on thebasis of chemical structure and/or chemical or physical properties. Acompound which is a derivative of an ingenane, pepluane or jatrophane isnevertheless encompassed by the present invention through use of theterms “ingenane”, “pepluane” or “jatrophane” since these terms includederivatives, chemical analogues and chemically synthetic forms of thesefamilies of compounds. One particularly preferred derivative is anangeloyl derivative of ingenane.

[0078] The preferred chemical agent of the present invention is onewhich exhibits an effect on a protein kinase C (PKC) enzyme. Such aneffect may be a direct activation or inhibition of PKC activity or adirect effect on the levels of PKC enzyme in a cell or exported from acell. Furthermore, the effect may be transitory or may involve aninitial activation of PKC activity or PKC enzyme synthesis or inductionof a functional conformation followed by a down-regulation of PKCactivity, enzyme levels or formation of a deactivated conformation.Consequently, an effect on PKC is regarded herein as a modulatory effectand is conveniently determined by consequential events such as resultingfrom altered signal transduction. For example, activation of latentvirus, activation of immune mechanisms or activation of a gene promotermay occur and this is regarded herein as a modulatory effect on PKC.

[0079] The chemical agents of the present invention may be in purifiedor isolated form meaning that the preparation is substantially devoid ofother compounds or contaminating agents other than diluent, solvent orcarrier or isoforms of the agents. Furthermore, the term “chemicalagent” includes preparations of two or more compounds either admixedtogether or co-purified from a particular source. The chemical agent mayalso be a chemical fraction, extract or other preparation from theEuphorbiaceace plant.

[0080] Consequently, reference herein to a “chemical agent” includes apurified form of one or more compounds or a chemical fraction or extractsuch as from the sap of a Euphorbiaceace plant, and in particular aspecies of Euphorbia, and most preferably from E. peplus or botanical orhorticultural relatives or variants thereof.

[0081] Accordingly, one aspect of the present invention contemplates amethod for the treatment or prophylaxis of a condition associated withthe presence of a biological entity or part thereof or a toxin or venomtherefrom or a genetic event caused thereby in a subject, said methodcomprising the administration to said subject of a symptom-amelioratingeffective amount of a chemical agent obtainable from a plant of theEuphorbiaceae family or a derivative or chemical analogue thereof whichchemical agent is a macrocyclic diterpene selected from compounds of theingenane, pepluane and jatrophane families and which chemical agent orderivative or chemical analogue is represented by any one of the generalformulae (I)-(V)

[0082] wherein:

[0083] n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides;

[0084] A-T are independently selected from hydrogen, R₁, R₂, R₃, F, Cl,Br, I, CN, OR₁, SR₁, NR₁R₂, N(═O)₂, NR₁OR₂, ONR₁R₂, SOR₁, SO₂R₁, SO₃R₁,SONR₁R₂, SO₂NR₁R₂, SO₃NR₁R₂, P(R₁)₃, P(═O)(R₁)₃, Si(R₁)₃, B(R₁)₂,(C═X)R₃ or X(C═X)R₃ where X is selected from sulfur, oxygen andnitrogen;

[0085] R₁ and R₂ are each independently selected from C₁-C₂₀ alkyl(branched and/or straight chained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl(branched and/or straight chained), C₂-C₁₀alkynyl (branched and/orstraight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₁, SR₁,NR₁R₂, N(═O)₂, NR₁OR₂, ONR₁R₂, SOR₁, SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂,SO₃NR₁R₂, P(R₁)₃, P(═O)(R₁)₃, Si(R₁)₃, B(R₁)₂]alkyl;

[0086] R₃ is selected from R₁, R₂, CN, COR₁, CO₂R₁, OR₁, SR₁, NR₁R₂,N(═O)₂, NR₁OR₂, ONR₁R₂, SOR₁, SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂, SO₃NR₁R₂,P(R₁)₃, P(═O)(R₁)₃, Si(R₁)₃, B(R₁)₂;

[0087] A connected to B (or C), D (or E), R (or Q), P (or O) or S (or T)is a selection of C₁-C₈ disubstituted (fused) saturated or unsaturatedcarbocyclic or heterocyclic rings further substituted by R₃, (C═X)R₃ andX(C═X)R₃, including epoxides and thioepoxides;

[0088] J connected to I (or H), G (or F), K (or L), M (or N) or S (or T)is a selection of C₁-C₈ disubstituted (fused) saturated and unsaturatedcarbocyclic or heterocyclic rings further substituted by R₃, (C═X)R₃ andX(C═X)R₃, including epoxides and thioepoxides;

[0089] D (or E) connected to B (or C) or G (or F); I (or H) connected toG (or F); P (or O) connected to R (or Q) or M (or N); K (or L) connectedto N (or M) is a selection of C₁-C₈ disubstituted (fused) saturated orunsaturated carbocyclic or heterocyclic rings substituted by R₃, (C═X)R₃and X(C═X)R₃, including epoxides and thioepoxides;

[0090] B and C, D and E, R and Q, P and O, I and H, G and F, K and L, Mand N or S and T are =X where X is selected from sulfur, oxygen,nitrogen, NR₁R₂, and ═CR₁R₂

[0091] wherein:

[0092] n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides;

[0093] A′-T′ are independently selected from hydrogen, R₄, R₅, R₆, F,Cl, Br, I, CN, COR₄, CO₂R₄, OR₄, SR₄, NR₄R₅, CONR₄R₅, N(═O)₂, NR₄OR₅,ONR₄R₅, SOR₄, SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅, SO₃NR₄R₅, P(R₄)₃,P(═O)(R₄)₃, Si(R₄)₃, B(R₄)₂, (C═X)R₆ or X(C═X)R₆ where X is selectedfrom sulfur, oxygen and nitrogen;

[0094] R₄ and R₅ are each independently selected from C₁-C₂₀ alkyl(branched and/or straight chained), C₁-C₂₀ arylalkyl, C₃-Cg cycloalkyl,C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl(branched and/or straight chained), C₂-C₁₀ alkynyl (branched and/orstraight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀alkoxyalkyl, C₁-C₁₀haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₄, SR₄,NR₄R₅, N(═O)₂, NR₄OR₅, ONR₄R₅, SOR₄, SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅,SO₃NR₄R₅, P(R₄)₃, P(═O)(R₄)₃, Si(R₄)₃, B(R₄)₂]alkyl;

[0095] R₆ is selected from R₄, R₅, CN, COR₄, CO₂R₄, OR₄, SR₄, NR₄R₅,N(═O)₂, NR₄OR₅, ONR₄R₅, SOR₄, SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅, SO₃NR₄R₅,P(R₄)₃, P(═O)(R₄)₃, Si(R₄)₃, B(R₄)₂;

[0096] E′ and R′ or H′ and O′ is a C₂-C₈ saturated or unsaturatedcarbocyclic or heterocyclic ring system further substituted by R₆,including epoxides and thioepoxides;

[0097] O′ connected to M′ (or N′) or Q′ (or P′); R′ connected to Q′ (orP′) or S′ (or T′); S′ (or T′) coimected to A′ (or B′); A′ (or B′)connected to C′ (or D′); E′ connected to C′ (or D′) or F′ (or G′); H′connected to I′; I′ connected to J′; J′ connected to K′; K′ connected toL′; L′ connected to M′ (or N′) are C₁-C₈ disubstituted (fused) saturatedor unsaturated carbocyclic or heterocyclic ring systems furthersubstituted by R₆, (C═X)R₆ and X(C═X)R₆, including epoxides andthioepoxides;

[0098] A′, B′ and C′, D′ and F′, G′ and M′, N′ and P′, Q′ and S′, T′ are=X where X is selected from sulfur, oxygen, nitrogen, NR₄R₅, (C═X)R₆,X(C═X)R₆, and ═CR₇R₈;

[0099] R₇ and R₈ are each independently selected from R₆, (C═X)R₆ andX(C═X)R₆

[0100] wherein:

[0101] n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides;

[0102] A¹-T¹ are independently selected from hydrogen, R₉, R₁₀, R₁₁, F,Cl, Br, I, CN, OR₉, SR₉, NR₉R₁₀, N(═O)₂, NR₉OR₁₀, ONR₉R₁₀, SOR₉, SO₂R₉,SO₃R₉, SONR₉R₁₀, SO₂NR₉R₁₀, SO₃NR₉R₁₀, P(R₉)₃, P(═O)(R₉)₃, Si(R₉)₃,B(R₉)₂, (C═X)R₁ or X(C═X)R₁₁ where X is selected from sulfur, oxygen andnitrogen;

[0103] R₉ and R₁₀ are each independently selected from C₁-C₂₀ alkyl(branched and straight chained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, C₁-C₁₋₄ heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl(branched and straight chained), C₂-C₁₀alkynyl (branched and straightchained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl,dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₉, SR₉, NR₉R₁₀,N(═O)₂, NR₉OR₁₀, ONR₉R₁₀, SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀, SO₂NR₉R₁₀,SO₃NR₉R₁₀, P(R₉)₃, P(═O)(R₉)₃, Si(R₉)₃, B(R₉)₂]alkyl;

[0104] R₁₁ is selected from R₉, R₁₀, CN, COR₉, CO₂R₉, OR₉, SR₉, NR₉R₁₀,N(═O)₂, NR₉OR₁₀, ONR₉R₁₀, SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀, SO₂NR₉R₁₀,SO₃NR₉R₁₀, P(R₉)₃, P(═O)(R₉)₃, Si(R₉)₃, B(R₉)₂;

[0105] B¹ and R₁, E¹ and Ö¹ and Ë¹ and M¹ are selected from a C₂-C₈saturated or unsaturated carbocyclic or heterocyclic ring system furthersubstituted by R₁₁, including epoxides and thioepoxides;

[0106] A¹ (or Ä¹) connected to Á¹ (or Ã¹) or T¹ (or S¹); B¹ connected toÁ¹ (or Ã¹) or C¹ (or D¹). E¹ connected to Ë¹ or C¹ (or D¹); Ë¹ connectedto É¹ (or F¹); G¹ (or H¹) connected to É¹ (or F¹) or I¹ (or J¹); K¹ (orL¹) connected to I¹ (or J¹) or M¹; M¹ connected to O¹ (or N¹); Ö¹connected O¹ (or N¹) or P¹ (or Q¹); R¹ connected P¹ (or Q¹) or S¹ (orT¹) are C₁-C₈ disubstituted (fused) saturated or unsaturated carbocyclicor heterocyclic ring systems further substituted by R₁₁, (C═X)R₁₁ andX(C═X)R₁₁, including epoxides and thioepoxides;

[0107] A¹, Ä and Á, Ã and C¹, D¹ and F¹, É and G¹, H¹ and I¹, J¹ and K¹,L¹ and N¹, O¹ and P¹, Q¹ and S¹, T¹ are =X where X is selected fromsulfur, oxygen, nitrogen, NR₉R₁₀, including (C═X)R₁₁ and X(C═X)R₁₁, and═CR₁₂R₁₃;

[0108] R₁₂ and R₁₃ are independently selected from R₁₁ , (C═X)R₁₁ andX(C═X)R₁₁

[0109] wherein:

[0110] n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides;

[0111] A²-X² are independently selected from hydrogen, R₁₄, R₁₅, R₁₆, F,Cl, Br, I, CN, OR₁₄, SR₄, NR₁₄R₁₅, N(═O)₂, NR₁₄R₁₅, ONR₁₄R₁₅, SOR₁₄,SO₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅, SO₂NR₁₄R₁₅, SO₃NR₁₄R₁₅, P(R₁₄)₃, P(═O)(R₁₄)₃,Si(R₁₄)₃, B(R₁₄), (C═Y)R₁₆ or Y(C═Y)R₁₆ where Y is selected from sulfur,oxygen and nitrogen;

[0112] R₁₄ and R₁₅ are each independently selected from C₁-C₂₀ alkyl(branched and/or straight chained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl(branched and/or straight chained), C₂-C₁₀ alkynyl (branched and/orstraight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₁₄,SR₁₄, NR₁₄R₁₀, N(═O)₂, NR₁₄OR₁₅, ONR₁₄R₁₅, SOR₁₄, SO₂R₁₄, SO₃R₁₄,SONR₁₄R₁₅, SO₂NR₁₄R₁₅, SO₃NR₁₄R₁₅, P(R₁₄)₃, P(═O)(R₁₄)₃, Si(R₁₄)₃,B(R₁₄)₂]alkyl;

[0113] R₁₆ is selected from R₁₄, R₁₅, CN, COR₁₄, CO₂R₁₅, OR₁₄, SR₁₄,NR₁₄R₁₅, N(═O)₂, NR₁₄OR₁₅, ONR₁₄R₁₅, SOR₁₄, SO₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅,SO₂NR₁₄R₁₅, SO₃NR₁₄R₁₅, P(R₁₄)₃, P(═O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄)₂;

[0114] E² and V², H² and S², and I² and P² are C₂-C₈ saturated orunsaturated carbocyclic or heterocyclic ring system further substitutedby R₁₆, including epoxides and thioepoxides;

[0115] A² (or B²) connected to C² (or D²) or W² (or X²); E² connected toC² (or D²) or F² (or G²); H² connected to F2 (or G²) or I²; I² connectedto J² (or K²); L² (or M²) connected to J² (or K²) or N² (or O₂); R² (orQ²) connected to P² or S²; V² connected to U² (or T²) or W² (or X²) areC₁-C₈ disubstituted (fused) saturated or unsaturated carbocyclic orheterocyclic ring systems further substituted by R₁₆, (C═Y)R₁₆ andY(C═Y)R₁₆, including epoxides and thioepoxides;

[0116] A², B²; C², D²; F², G²; J², K²; L², M²; N², O²; Q², R²; U², T²and X², W² are =Y where Y is selected from sulfur, oxygen, nitrogen,NR₁₄R₁₅ and ═CR₁₇R₁₈;

[0117] R₁₇ and R₁₈ are independently selected from R₁₆, (C═Y)R₁₆ andY(C═Y)R₁₆

[0118] wherein:

[0119] n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides;

[0120] A³-Z³ are independently selected from hydrogen, R₁₉, R₂₀, R₂₁, F,Cl, Br, I, CN, OR₁₉, SR₁₉, NR₁₉R₂₀, N(═O)₂, NR₁₉OR₂₀, ONR₁₉R₂₀, SOR₁₉,SO₂R₉ ₉, SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀, P(R₁₉)₃,P(═O)(R₁₉)₃, Si(R₁₉)₃, B(R₁₉)₂, (C=Ø)R₂₁ or Ø(C=Ø)R₂₁ where Ø is sulfur,oxygen and nitrogen;

[0121] R₁₉ and R₂₀ are each independently selected from C₁-C₂₀ alkyl(branched and/or straight chained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl(branched and/or straight chained), C₂-C₁₀ alkynyl (branched and/orstraight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₁₉,SR₁₉, NR₁₉R₂₀, N(═O)₂, NR₁₉OR₂₀, ONR₁₉R₂₀, SOR₁₉, SO₂R₁₉, SO₃R₁₉,SONR₁₉R₂₀, SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀, P(R₁)₃, P(═O)(R₁₉)₃, Si(R₁₉)₃,B(R₁₉)₂]alkyl;

[0122] R₂₁ is selected from R₁₉, R₂₀, CN, COR₁₉, CO₂R₁₉, OR₁₉, SR₁₉,NR₁₉R₂₀, N(═O)₂, NR₁₉OR₂₀, ONR₁₉R₂₀, SOR₁₉, SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀,SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀, P(R₁₉)₃, P(═O)(R₁₉)₃, Si(R₁₉)₃, B(R₁₉)₂;

[0123] D³ connected to X³ is a C₂-C₈ saturated or unsaturatedcarbocyclic or heterocyclic ring system further substituted by R₂₁,including epoxides and thioepoxides;

[0124] A³ (or Ä³) connected to B³ (or C³) or Z³ (or Y³); D³ connected toB³ (or C³) or E³ (or F³; G³ (or H³) connected to E³ (or F³) or I³ (orJ³); L³ (or K³) connected to I³ (or J³) or M³ (or N³); O³ (or Ö³)connected to N³ (or M³) or P³ (or Q³). S³ (or R³) connected to Q³ (orP³) or U³ (or T³). W³ (or Y³) connected to U³ (or T³) or X³; X³connected to Y³ (or Z³) are C₁-C₈ disubstituted (fused) saturated orunsaturated carbocyclic or heterocyclic ring systems further substitutedby R₂₁, (C=Ø)R₂₁ and Ø (C=Ø)R₂₁, including epoxides and thioepoxides;

[0125] A³, Ä3; B³, C³; E³, F³; G³, H³; I³, J³; K³, L³; M³, N³; O³, Ö³;Q³, P³, S³, R³, U³, T³, W³, V³, and Z³, Y³ are =Ø where Ø is selectedfrom sulfur, oxygen, nitrogen, NR₁₉R₂₀, and ═CR₂₂R₂₃; and

[0126] R₂₂ and R₂₃ are selected from R₂₁, (C=Ø)R₂₁ and Ø(C=Ø)R₂₁;

[0127] and which chemical agent or derivative or chemical analoguethereof is capable of modulating PKC activity, PKC-dependent geneexpression or PKC enzyme turnover and wherein said chemical agent or itsderivatives or chemical analogues is administered for a time and underconditions sufficient to ameliorate one or more symptoms associated withsaid biological entity.

[0128] Especially preferred chemical agents or derivatives or chemicalanalogues thereof are represented by the general formula (VI):

[0129] wherein:

[0130] R₂₄, R₂₅ and R₂₆ are independently selected from hydrogen, R₂₇,R₂₈, F, Cl, Br, I, CN, OR₂₇, SR₂₇, NR₂₇R₂₈, N(═O)₂, NR₂₇OR₂₈, ONR₂₇R₂₈,SOR₂₇, SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃,P(═O)(R₂₇)₃, Si(R₂₇)₃, B(R₂₇)₂, (C═X)R₂₉ or X(C═X)R₂₉ where X isselected from sulfur, oxygen and nitrogen;

[0131] R₂₇ and R₂₈ are each independently selected from C₁-C₂₀ alkyl(branched and/or straight chained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl(branched and/or straight chained), C₂-C₁₀ alkynyl (branched and/orstraight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₂₇,SR₂₇, NR₂₇R₂₈, N(═O)₂, NR₂₇OR₂₈, ONR₂₇R₂₈, SOR₂₇, SO₂R₂₇, SO₃R₂₇,SONR₂₇R₂₈, SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃, P(═O)(R₂₇)₃, Si(R₂₇)₃,B(R₂₇)₂]alkyl;

[0132] R₂₉ is selected from R₂₇, R₂₈, CN, COR₂₇, CO₂R₂₇, OR₂₇, SR₂₇,NR₂₇R₂₈, N(═O)₂, NR₂₇OR₂₈, ONR₂₇R₂₈, SOR₂₇, SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈,SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃, P(═O)(R₂₇)₃, Si(R₂₇)₃, B(R₂₇)₂.

[0133] In a preferred embodiment, R₂₄ is hydrogen, OAcetyl or OH.

[0134] In another preferred embodiment, R₂₅ and R₂₆ are OH.

[0135] As used herein, the term “alkyl” refers to linear or branchedchains. The term “haloalkyl” refers to an alkyl group substituted by atleast one halogen. Similarly, the term “haloalkoxy” refers to an alkoxygroup substituted by at least one halogen. As used herein the term“halogen” refers to fluorine, chlorine, bromine and iodine.

[0136] As used herein the term “aryl” refers to aromatic carbocyclicring systems such as phenyl or naphthyl, anthracenyl, especially phenyl.Suitably, aryl is C₆-C₁₄ with mono, di- and tri-substitution containingF, Cl, Br, I, NO₂, CF₃, CN, OR₁, COR₁, CO₂R₁, NHR₁, NR₁R₂, NR₁OR₂,ONR₁R₂, SOR₁, SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂, SO₃NR₁R₂, P(R₁)₃,P(═O)(R₁)₃, Si(R₁)₃, B(R₁)₂, wherein R₁ and R₂ are defined above

[0137] As used herein the terms “heterocycle”, “heterocyclic”,“heterocyclic systems” and the like refer to a saturated, unsaturated,or aromatic carbocyclic group having a single ring, multiple fused rings(for example, bicyclic, tricyclic, or other similar bridged ring systemsor substituents), or multiple condensed rings, and having at least oneheteroatom such as nitrogen, oxygen, or sulfur within at least one ofthe rings. This term also includes “heteroaryl” which refers to aheterocycle in which at least one ring is aromatic. Any heterocyclic orheteroaryl group can be unsubstituted or optionally substituted with oneor more groups, as defined above. Further, bi- or tricyclic heteroarylmoieties may comprise at least one ring, which is either completely, orpartially, saturated. Suitable heteroaryl moieties include, but are notlimited to oxazolyl, thiazaoyl, thienyl, furyl, 1-isobenzofuranyl,3H-pyrrolyl, 2H-pyrrolyl, N-pyrrolyl, imidazolyl, pyrazolyl,isothiazolyl, isooxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyradazinyl,indolizinyl, isoindolyl, indoyl, indolyl, purinyl, phthalazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazoyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3,4-oxatriazolyl,1,2,3,5-oxatriazolyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,azepinyl, oxepinyl, thiepinyl, benzofuranyl, isobenzofuranyl,thionaphthenyl, isothionaphthenyl, indoleninyl, 2-isobenzazolyl,1,5-pyrindinyl, pyrano[3,4-b]pyrrolyl, isoindazolyl, indoxazinyl,benzoxazolyl, anthranilyl, quinolinyl, isoquinolinyl, cinnolinyl,quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridinyl, andpyrido[3,2-b]pyridinyl, pyrido[4,3-b]pyridinyl.

[0138] Reference to a biological entity includes a prokaryoticmicroorganism, a lower eukaryotic microorganism, a complex eukaryoticorganism or a virus.

[0139] A prokaryotic microorganism includes bacteria such as Grampositive, Gram negative and Gram variable bacteria and intracellularbacteria. Examples of bacteria contemplated herein include the speicesof the genera Treponema sp., Borrelia sp., Neisseria sp., Legionellasp., Bordetella sp., Escherichia sp., Salmonella sp., Shigella sp.,Klebsiella sp., Yersinia sp., Vibrio sp., Hemophilus sp., Rickettsiasp., Chlamydia sp., Mycoplasma sp., Staphylococcus sp., Streptococcussp., Bacillus sp., Clostridium sp., Corynebacterium sp.,Proprionibacterium sp., Mycobacterium sp., Ureaplasma sp. and Listeriasp.

[0140] Particularly preferred species include Treponema pallidum,Borrelia burgdorferi, Neisseria gonorrhea, Neisseria meningitidis,Legionella pneumophila, Bordetella pertussis, Escherichia coli,Salmonella typhi, Salmonella typhimurium, Shigella dysenteriae,Klebsiella pneumoniae, Yersinia pestis, Vibrio cholerae, Hemophilusinfluenzae, Rickettsia rickettsii, Chlamydia trachomatis, Mycoplasmapneumoniae, Staphylococcus aureus, Streptococcus pneumoniae,Streptococcus pyogenes, Bacillus anthracis, Clostridium botulinum,Clostridium tetani, Clostridium perfringens, Corynebacteriumdiphtheriae, Proprionibacterium acnes, Mycobacterium tuberculosis,Mycobacterium leprae and Listeria monocytogenes.

[0141] A lower eukaryotic organism includes a yeast or fungus such asbut not limited to Pneumocystis carinii, Candida albicans, Aspergillus,Histoplasma capsulatum, Blastomyces dermatitidis, Cryptococcusneoformans, Trichophyton and Microsporum.

[0142] A complex eukaryotic organism includes worms, insects, arachnids,nematodes, aemobe, Entamoeba histolytica, Giardia lamblia, Trichomonasvaginalis, Trypanosoma brucei gambiense, Trypanosoma cruzi, Balantidiumcoli, Toxoplasma gondii, Cryptosporidium or Leishmania.

[0143] The term “viruses” is used in its broadest sense to includeviruses of the families adenoviruses, papovaviruses, herpesviruses:simplex, varicella-zoster, Epstein-Barr, CMV, pox viruses: smallpox,vaccinia, hepatitis B, rhinoviruses, hepatitis A, poliovirus,rubellavirus, hepatitis C, arboviruses, rabiesvirus, influenzaviruses Aand B, measlesvirus, mumpsvirus, HIV, HTLV I and II.

[0144] Particularly preferred prokaryotic microorganisms are Salmonellasp. and other enteric microorganisms and Streptococcus sp. andStaphylococcus sp. Particularly preferred lower eukaryotic organismsinclude species of Trichophytos, Microsporum and Epidermophytos, yeastand Plasmodium sp. such as malaria agents.

[0145] Preferred complex eukaroytic organisms are insects such asblood-sucking insects.

[0146] Preferred viruses are HIV, EBV and CMV.

[0147] As stated above, the present invention extends to the use of thesubject chemical agents to not only directly remove, destroy or reducethe levels of the entity but also of any molecule associated therewithsuch as toxins and venoms. The agents may act directly on the agent orindirectly via, for example, activation of the immune system and/oractivation of latent viruses.

[0148] In one particular embodiment, the condition to be treated isassociated with a prokaryotic microorganism.

[0149] Accordingly, another aspect of the present invention contemplatesa method for the treatment or prophylaxis of a microbial infection in asubject, said method comprising the administration to said subject of asymptom-ameliorating effective amount of a macrocyclic diterpene, or achemical fraction comprising same from a plant of the familyEuphorbiaceae or a derivative or chemical analogue of said macrocyclicditerpene having the structures as defined above wherein saidmacrocyclic diterpene or its derivative or chemical analogue modulatesPKC activity, synthesis or enzyme turnover, said administration beingfor a time and under conditions sufficient to ameliorate one or moresymptoms of the infection.

[0150] The preferred microorganism in this context includes but is notlimited to Salmonella sp., Streptococcus sp. and Staphylococcus sp.

[0151] A “symptom” includes sickness, bacterial loads in particularspecimens associated illness (e.g. headaches, lethargy, rashes, fever),septicemia, bacteremia and inflammation.

[0152] In another embodiment, the entity is a lower eukaryotic organism.

[0153] Accordingly, another aspect of the present invention provides amethod for the treatment or prophylaxis of an infection by a lowereukaryotic organism in a subject, said method comprising theadministration to said subject of a symptom-ameliorating effectiveamount of a macrocyclic diterpene or chemical fraction comprising samefrom a plant of the family Euphorbiaceae or a derivative or chemicalanalogue of said macrocyclic diterpene having the structures as definedabove wherein said macrocyclic diterpene or its derivative or chemicalanalogue modulates PKC activity, synthesis or enzyme turnover, saidadministration being for a time and under conditions sufficient toameliorate one or more symptoms of the infection.

[0154] Preferably, the lower eukaryotic organism is a yeast or fungisuch as but not limited to Pneumocystis carinii, Candida albicans,Aspergillus, Histoplasma capsulatum, Blastomyces dermatitidis,Cryptococcus neoformans, Trichophyton and Microsporim.

[0155] Particularly preferred lower eukaryotic organisms are yeasts,fungi and a Plasmodium sp.

[0156] The term “symptom” is as stated above except in relation toeukaryotic organism.

[0157] In yet another embodiment, the entity is a complex eukaryoticorganism.

[0158] Accordingly, another aspect of the present invention provide amethod for the treatment or prophylaxis of an infection by a complexeukaryotic organism in a subject, said method comprising theadministration to said subject of a symptom-ameliorating effectiveamount of a macrocyclic diterpene, or a chemical fraction comprisingsame from a plant of the family Euphorbiaceae or a derivative orchemical analogue of said macrocyclic diterpene having the structures asdefined above wherein said macrocyclic diterpene or its derivative orchemical analogue modulates PKC activity, synthesis or enzyme turnover,said administration being for a time and under conditions sufficient toameliorate one or more symptoms of the infection.

[0159] Preferably, the complex eukaryotic organism is a worm, insect,arachnid, nematode, aemobe, Entamoeba histolytica, Giardia lamblia,Trichomonas vaginalis, Trypanosoma brucei gambiense, Trypanosoma cruzi,Balantidium coli, Plasmodium malariae, Plasmodium tropicalis, Toxoplasmagondii, Cryptosporidium or Leishmania.

[0160] In yet another embodiment, the entity is a virus.

[0161] Accordingly, another aspect of the present invention provide amethod for the treatment or prophylaxis of an infection by a virus in asubject, said method comprising the administration to said subject of asymptom-ameliorating effective amount of a macrocyclic diterpene, or achemical fraction comprising same from a plant of the familyEuphorbiaceae or a derivative or chemical analogue of said macrocyclicditerpene having the structures as defined above wherein saidmacrocyclic diterpene or its derivative or chemical analogue modulatesPKC activity, synthesis or enzyme turnover, said administration beingfor a time and under conditions sufficient to ameliorate one or moresymptoms of the infection.

[0162] Preferred viruses include adenoviruses, papovaviruses,herpesviruses: simplex, varicella-zoster, Epstein-Barr, CMV, poxviruses: smallpox, vaccinia, hepatitis B, rhinoviruses, hepatitis A,poliovirus, rubellavirus, hepatitis C, arboviruses, rabiesvirus,influenzaviruses A and B, measlesvirus, mumpsvirus, HIV, HTLV I and II.

[0163] This aspect of the present invention is particularly useful inthe treatment of latent virus infection. The term “latent virus”includes reference to a virus or more particularly a virus genome orpart thereof which has integrated into the genome of a cell. When in thelatent state, it is more difficult for a host's immune system torecognize a virus as a foreign body. In accordance with the presentinvention, it is proposed that the subject chemical agents are capableof activating a latent virus thereby causing the virus to undergoreplication and at least partial assembly. As a result, a mechanismwithin the host or within the cells of the host is then induced toassist in the eradication of the virus. The present invention extends toboth the direct effect of the chemical agent on the virus as well aspromoting the immune system to direct same against the virus and tocombination therapies with anti-viral agents.

[0164] Accordingly, another aspect of the present invention contemplatesa method for the treatment or prophylaxis of infection by a latent virusin a subject, said method comprising the administration to said subjectof a virus activating effective amount of a macrocyclic diterpene, or achemical fraction comprising same from a plant of the familyEuphorbiaceae or a derivative or chemical analogue of said macrocyclicditerpene having the structures as defined above wherein saidmacrocyclic diterpene or its derivative or chemical analogue modulatesPKC activity, synthesis or enzyme turnover, said administration beingfor a time and under conditions sufficient to activate said virus.

[0165] The activated virus is then destroyed or removed by the host'sown immune system and/or by anti-viral chemotherapy or by the effects ofthe agents themselves.

[0166] In a preferred embodiment, the method further comprises thesimultaneous, sequential or separate administration of an ancillaryagent which destroys or attenuates a replicating virus, in combinationwith the macrocyclic diterpene or chemical fraction. Thus, the inventioncontemplates the combined use of a macrocyclic diterpene or chemicalfraction which activates a latent virus to thereby cause the virus toundergo replication, and the use of an ancillary agent which eradicatesthe replicating virus.

[0167] Accordingly, in another aspect, the invention encompasses amethod for the treatment or prophylaxis of infection by a latent virusin a subject, said method comprising the simultaneous, sequential orseparate administration to said subject of a virus-activating effectiveamount of a macrocyclic diterpene, or a chemical fraction comprisingsame from a plant of the family Euphorbiaceae or a derivative orchemical analogue of said macrocyclic diterpene having the structures asdefined above wherein said macrocyclic diterpene or its derivative orchemical analogue modulates PKC activity, synthesis or enzyme turnover,together with a virus-destroying or -attenuating effective amount of anancillary agent which destroys or attenuates a replicating form of saidvirus, said administration being for a time and under conditionssufficient for said macrocyclic diterpene or chemical fraction toactivate said virus to thereby cause the virus to undergo replicationand for said ancillary agent to destroy or attenuate said replicatingvirus.

[0168] In one embodiment, the latent virus is HIV. A range of HIVspecific agents may be used for its destruction or attenuation,including, for example, the agents described in Matsuhita et al., 2000.Preferred HIV specific ancillary agents include, for example, nucleosideanalogues such as combivir, epivir, hivid, retrovir, videx, zerat andzygen, non-nucleoside agents such as rescriptor, sustiva and viramune,adjunctive anti-retrovirals such as hydrea and droxa, and proteaseinhibitors such as agenerase, fortovase, crixivan, invirase, norvir andvirasept.

[0169] In another embodiment, the latent virus is EBV. Preferred EBVspecific ancillary agents are selected from ganciclovir (GVC) or3′-azido-3′deoxythymidine (AZT), as for example disclosed by Westphal etal., 2000.

[0170] In yet another embodiment, the latent virus is CMV. A preferredCMV specific ancillary agent is cidofovir, as for example disclosed byPlatzbecker et al., 2001.

[0171] Particularly useful compounds include5,8,9,10,14-pentaacetoxy-3-benzoyloxy-15-hydroxypepluane (pepluane),derivatives of said pepluane, jatrophanes of Conformation II including2,3,5,7,15-pentaacetoxy-9-nicotinoyloxy-14-oxojatropha-6(17),11E-diene(jatrophane 1), derivatives of said jatrophane 1,2,5,7,8,9,14-hexaacetoxy-3-benzoyloxy-15-hydroxy-jatropha-6(17),11E-diene(atrophane 2), derivatives of said jatrophane 2,2,5,14-triacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxy-9-nicotinoyloxyjatropha-6(17),11E-diene(atrophane 3), derivatives of said jatrophane 3,2,5,9,14-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxyjatropha-6(17),11E-diene(jatrophane 4), derivatives of said jatrophane 4,2,5,7,14-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-9-nicotinoyloxyjatropha-6(17),11E-diene(jatrophane 5), derivatives of said jatrophane 5,2,5,7,9,14-pentaacetoxy-3-benzoyloxy-8,15-dihydroxyjatropha-6(17),11E-diene(jatrophane 6), derivatives of said jatrophane 6, or pharmaceuticallyacceptable salts of these.

[0172] Even more particularly preferred compounds are angeloylsubstituted ingenanes or derivatives thereof such as ingenol-3-angelate,20-hydroxy-ingenol-3-angelate, 20-O-acetyl-ingenol-3-angelate, orderivatives of said angelates, or pharmaceutically acceptable salts ofthese.

[0173] Still a further aspect of the present invention contemplates amethod of assessing the suitability of a chemical agent fromEuphorbiaceae for the practice of the present invention. Numericalvalues are assigned to chemical agents including fractions comprisingthe chemical agents as set forth, for example, in Table A: TABLE AFeature Value An ability to modulate PKC activity or effect +1 Anability to induce bipolar dendritic activity +1 An ability to displacephorbol dibutyrate from binding to PKC +1 An ability to inducerespiratory burst in leucocytes +1 An ability to stimulate phagocytosisin peripheral +1 blood mononuclear cells An ability to be derived from amember of the +1 Euphorbiaceae family Derived from E. peplus +3 Waterextractible from the sap of Euphorbia sp. +2 An ability to activatelatent virus +4 A lower tumor promotion activity than TPA/PMA +2

[0174] The value for each feature is referred to as the Index Value(I_(V)).

[0175] The sum of I_(V), i.e. ΣI_(V), provides a potency of agent(P_(A)) value and this enables an analytical approach to screening andselecting compounds from Euphorbiaceae useful in the practice of thepresent invention.

[0176] In one example, 20-acetyl-ingenol-3 angelate exhibits aP_(A)=ΣI_(V)=15.

[0177] Accordingly, another aspect of the present invention contemplatesa method for the treatment or prophylaxis of infection or colonizationor presence of a biological entity in a subject, said method comprisingadministration to said subject of a symptom-ameliorating effectiveamount of a macrocyclic diterpene obtainable from a Euphorbiaceae plantor its botanical or horticultural relative, said macrocyclic diterpenebeing selected from an ingenane, pepluane or jatrophane, or a derivativeor chemical analogue thereof, having the structure represented by anyone of the general formulae (I)-(V) as defined above and wherein saidchemical agent exhibits a potency of agent (P_(A)) of >10, wherein theP_(A)=ΣI_(V) where I_(V) is a numerical value associated with aparticular feature as listed below: Feature Value An ability to modulatePKC activity or effect +1 An ability to induce bipolar dendriticactivity +1 An ability to displace phorbol dibutyrate from binding toPKC +1 An ability to induce respiratory burst in leucocytes +1 Anability to stimulate phagocytosis in peripheral +1 blood mononuclearcells An ability to be derived from a member of the +1 Euphorbiaceaefamily Derived from E. peplus +3 Water extractible from the sap ofEuphorbia sp. +2 Activity against latent virus +4

[0178] or pharmaceutically acceptable salts of these, said chemicalagent being administered for a time and under conditions sufficient toameliorate at least one symptom caused by or associated with thebiological entity.

[0179] Preferred compounds are selected from the list comprising:

[0180] 5,8,9,10,14-pentaacetoxy-3-benzoyloxy-15-hydroxypepluane(pepluane);

[0181]2,3,5,7,15-pentaacetoxy-9-nicotinoyloxy-14-oxojatropha-6(17),11E-diene(jatrophane 1);

[0182]2,5,7,8,9,14-hexaacetoxy-3-benzoyloxy-15-hydroxy-jatropha-6(17),11E-diene(jatrophane 2);

[0183]2,5,14-triacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxy-9-nicotinoyloxyjatropha-6(17),11E-diene (jatrophane 3);

[0184]2,5,9,14-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxy-jatropha-6(17),11E-diene(jatrophane 4);

[0185]2,5,7,14-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-9-nicotinoyloxy-jatropha-6(17),11E-dienekjatrophane 5);

[0186]2,5,7,9,14-pentaacetoxy-3-benzoyloxy-8,15-dihydroxyjatropha-6(17),11E-diene (jatrophane 6);

[0187] 20-O-acetyl-ingenol-3-angelate, derivatives of20-O-acetyl-ingenol-3-angelate.

[0188] 20-hydroxy-ingelol-3-angelate, derivatives of20-hydroxy-ingenol-3-angelate; and

[0189] ingenol-3-angelate, derivatives of ingenol-3-angelate.

[0190] Preferably, the biological entity is a microorganism, virus,yeast, fungus, insect, arachnid or Plasmodium sp.

[0191] Reference herein to a subject includes a human, primate,livestock animal (e.g. sheep, cow, horse, pig, goat, donkey), laboratorytest animal (e.g. mouse, rat, guinea pig, hamster), companion animal(e.g. dog, cat) or avian species such as poultry birds (e.g. chicken,ducks, turkeys, geese) or game birds (e.g. arid ducks, pheasants).

[0192] The preferred subject is a human or primate or laboratory testanimal.

[0193] The most preferred subject is a human.

[0194] The ability to assign numerical values to certain characteristicsenables data processing means to assess the likely usefulness of aparticular compound or group of compounds forming a chemical agent.

[0195] The assessment of the suitability of a compound or group ofcompounds for the practice of the present invention is suitablyfacilitated with the assistance of a computer programmed with software,which inter alia adds index values (I_(v)) for at least two featuresassociated with the compound(s) to provide a potency value (P_(A))corresponding to the effectiveness of the compound(s) for treating orpreventing infection or colonization or presence of a biological entityin a subject. The compound features can be selected from:

[0196] (a) the ability to modulate PKC activity or effect;

[0197] (b) the ability to induce bipolar dendritic activity;

[0198] (c) the ability to be derived from a member of the Euphorbiaceaefamily;

[0199] (d) the ability to be derived from E. peplus;

[0200] (e) the ability to be water extractable from the sap of aEuphorbia species; or

[0201] (f) the ability to activate latent virus;

[0202] (g) less tumor promoting capacity than TPA or PMA.

[0203] Accordingly, in accordance with the present invention, indexvalues for such features are stored in a machine-readable storagemedium, which is capable of processing the data to provide a potencyvalue for a compound or group of compounds of interest.

[0204] Thus, in another aspect, the invention contemplates a computerprogram product for assessing the likely usefulness of a candidatecompound or group of compounds for treating or preventing infection orcolonization or presence of a biological entity in a subject, saidproduct comprising:

[0205] (1) code that receives as input index values for at least twofeatures associated with said compound(s), wherein said features areselected from:

[0206] (a) the ability to modulate PKC activity or effect;

[0207] (b) the ability to induce bipolar dendritic activity;

[0208] (c) the ability to be derived from a member of the Euphorbiaceaefamily;

[0209] (d) the ability to be derived from E. peplus;

[0210] (e) the ability to be water extractable from the sap of aEuphorbia species; or

[0211] (f) the ability to activate latent virus;

[0212] (g) less tumor promoting capacity than TPA or PMA;

[0213] (4) code that adds said index values to provide a sumcorresponding to a potency value for said compound(s); and

[0214] (5) a computer readable medium that stores the codes.

[0215] In a preferred embodiment, the computer program product comprisescode that assigns an index value for each feature of a compound or groupof compounds. In an especially preferred embodiment, index values areassigned as set forth in Table A above.

[0216] In a related aspect, the invention extends to a computer forassessing the likely usefulness of a candidate compound or group ofcompounds for treating or preventing infection or colonization orpresence of a biological entity in a subject, wherein said computercomprises:

[0217] (1) a machine-readable data storage medium comprising a datastorage material encoded with machine-readable data, wherein saidmachine-readable data comprise index values for at least two featuresassociated with said compound(s), wherein said features are selectedfrom:

[0218] (a) the ability to modulate PKC activity or effect;

[0219] (b) the ability to induce bipolar dendritic activity;

[0220] (c) the ability to be derived from a member of the Euphorbiaceaefamily;

[0221] (d) the ability to be derived from E. peplus;

[0222] (e) the ability to be water extractable from the sap of aEuphorbia species; or

[0223] (f) the ability to activate latent virus;

[0224] (g) less tumor promoting capacity than TPA or PMA;

[0225] (2) a working memory for storing instructions for processing saidmachine-readable data;

[0226] (3) a central-processing unit coupled to said working memory andto said machine-readable data storage medium, for processing saidmachine readable data to provide a sum of said index valuescorresponding to a potency value for said compound(s); and

[0227] (4) an output hardware coupled to said central processing unit,for receiving said potency value.

[0228] A version of these embodiments is presented in FIG. 8, whichshows a system 10 including a computer 11 comprising a centralprocessing unit (“CPU”) 20, a working memory 22 which may be, e.g. RAM(random-access memory) or “core” memory, mass storage memory 24 (such asone or more disk drives or CD-ROM drives), one or more cathode-ray tube(“CRT”) display terminals 26, one or more keyboards 28, one or moreinput lines 30, and one or more output lines 40, all of which areinterconnected by a conventional bidirectional system bus 50.

[0229] Input hardware 36, coupled to computer 11 by input lines 30, maybe implemented in a variety of ways. For example, machine-readable dataof this invention may be inputted via the use of a modem or modems 32connected by a telephone line or dedicated data line 34. Alternativelyor additionally, the input hardware 36 may comprise CD. Alternatively,ROM drives or disk drives 24 in conjunction with display terminal 26,keyboard 28 may also be used as an input device.

[0230] Output hardware 46, coupled to computer 11 by output lines 40,may similarly be implemented by conventional devices. By way of example,output hardware 46 may include CRT display terminal 26 for displaying asynthetic polynucleotide sequence or a synthetic polypeptide sequence asdescribed herein. Output hardware might also include a printer 42, sothat hard copy output may be produced, or a disk drive 24, to storesystem output for later use.

[0231] In operation, CPU 20 coordinates the use of the various input andoutput devices 36,46 coordinates data accesses from mass storage 24 andaccesses to and from working memory 22, and determines the sequence ofdata processing steps. A number of programs may be used to process themachine readable data of this invention. Exemplary programs may use forexample the following steps:

[0232] (1) inputting input index values for at least two featuresassociated with said compound(s), wherein said features are selectedfrom:

[0233] (a) the ability to modulate PKC activity or effect;

[0234] (b) the ability to induce bipolar dendritic activity;

[0235] (c) the ability to be derived from a member of the Euphorbiaceaefamily;

[0236] (d) the ability to be derived from E. peplus;

[0237] (e) the ability to be water extractable from the sap of aEuphorbia species; or

[0238] (f) the ability to activate latent virus;

[0239] (g) less tumor promoting capacity than TPA or PMA;

[0240] (2) adding the index values for said features to provide apotency value for said compound(s); and (3) outputting said potencyvalue.

[0241]FIG. 9 shows a cross section of a magnetic data storage medium 100which can be encoded with machine readable data, or set of instructions,for designing a synthetic molecule of the invention, which can becarried out by a system such as system 10 of FIG. 10. Medium 100 can bea conventional floppy diskette or hard disk, having a suitable substrate101, which may be conventional, and a suitable coating 102, which may beconventional, on one or both sides, containing magnetic domains (notvisible) whose polarity or orientation can be altered magnetically.Medium 100 may also have an opening (not shown) for receiving thespindle of a disk drive or other data storage device 24. The magneticdomains of coating 102 of medium 100 are polarized or oriented so as toencode in manner which may be conventional, machine readable data suchas that described herein, for execution by a system such as system 10 ofFIG. 8.

[0242]FIG. 10 shows a cross section of an optically readable datastorage medium 110 which also can be encoded with such amachine-readable data, or set of instructions, for designing a syntheticmolecule of the invention, which can be carried out by a system such assystem 10 of FIG. 8. Medium 110 can be a conventional compact disk readonly memory (CD-ROM) or a rewritable medium such as a magneto-opticaldisk, which is optically readable and magneto-optically writable. Medium100 preferably has a suitable substrate 111, which may be conventional,and a suitable coating 112, which may be conventional, usually of oneside of substrate 111.

[0243] In the case of CD-ROM, as is well known, coating 112 isreflective and is impressed with a plurality of pits 113 to encode themachine-readable data. The arrangement of pits is read by reflectinglaser light off the surface of coating 112. A protective coating 114,which preferably is substantially transparent, is provided on top ofcoating 112.

[0244] In the case of a magneto-optical disk, as is well known, coating112 has no pits 113, but has a plurality of magnetic domains whosepolarity or orientation can be changed magnetically when heated above acertain temperature, as by a laser (not shown). The orientation of thedomains can be read by measuring the polarisation of laser lightreflected from coating 112. The arrangement of the domains encodes thedata as described above.

[0245] The present invention further extends to pharmaceuticalcompositions useful in treating a pathogenic infection. In this regard,the chemical agents of the invention can be used as actives for thetreatment or prophylaxis of a condition associated with the presence ofa biological entity or part thereof or toxin or venom therefrom or agenetic event caused thereby in a subject. The chemical agents can beadministered to a patient either by themselves, or in pharmaceuticalcompositions where they are mixed with a suitable pharmaceuticallyacceptable carrier.

[0246] Accordingly, the invention also provides a composition fortreatment and/or prophylaxis of a condition associated with the presenceof a biological entity or part thereof or toxin or venom therefrom or agenetic event caused thereby in a subject, comprising one or morechemical agents of the invention, together with a pharmaceuticallyacceptable carrier and/or diluent.

[0247] Depending on the specific conditions being treated, chemicalagents may be formulated and administered systemically or locally.Techniques for formulation and administration may be found in“Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa.,latest edition. Suitable routes may, for example, include oral, rectal,transmucosal, or intestinal administration; parenteral delivery,including intramuscular, subcutaneous, intramedullary injections, aswell as intrathecal, direct intraventricular, intravenous,intraperitoneal, intranasal, or intraocular injections. For injection,the chemical agents of the invention may be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHanks' solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, penetrants appropriate to the barrier to bepermeated are used in the formulation. Such penetrants are generallyknown in the art. Intra-muscular and subcutaneous injection isappropriate, for example, for administration of immunomodulatorycompositions and vaccines.

[0248] The chemical agents can be formulated readily usingpharmaceutically acceptable carers well known in the art into dosagessuitable for oral administration. Such carriers enable the compounds ofthe invention to be formulated in dosage forms such as tablets, pills,capsules, liquids, gels, syrups, slurries, suspensions and the like, fororal ingestion by a patient to be treated. These carriers may beselected from sugars, starches, cellulose and its derivatives, malt,gelatine, talc, calcium sulphate, vegetable oils, synthetic oils,polyols, alginic acid, phosphate buffered solutions, emulsifiers,isotonic saline, and pyrogen-free water.

[0249] Pharmaceutical compositions suitable for use in the presentinvention include compositions wherein the active ingredients arecontained in an effective amount to achieve their intended purpose. Thedose of agent administered to a patient should be sufficient to effect abeneficial response in the patient over time such as a reduction in thesymptoms associated with the presence of a biological entity or partthereof or toxin or venom therefrom or a genetic event caused thereby ina subject. The quantity of the agent(s) to be administered may depend onthe subject to be treated inclusive of the age, sex, weight and generalhealth condition thereof. In this regard, precise amounts of theagent(s) for administration will depend on the judgement of thepractitioner. In determining the effective amount of the chemical agentto be administered in the treatment or prophylaxis of a conditionassociated with the biological entity, the physician may evaluate tissueor fluid levels of the biological entity, and progression of thedisorder. In any event, those of skill in the art may readily determinesuitable dosages of the chemical agents of the invention.

[0250] Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

[0251] Pharmaceutical preparations for oral use can be obtained bycombining the active compounds with solid excipient, optionally grindinga resulting mixture, and processing the mixture of granules, afteradding suitable auxiliaries, if desired, to obtain tablets or drageecores. Suitable excipients are, in particular, fillers such as sugars,including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as., for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinyl-pyrrolidone (PVP). If desired, disintegrating agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate. Such compositions may beprepared by any of the methods of pharmacy but all methods include thestep of bringing into association one or more chemical agents asdescribed above with the carrier which constitutes one or more necessaryingredients. In general, the pharmaceutical compositions of the presentinvention may be manufactured in a manner that is itself known, e.g. bymeans of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or lyophilisingprocesses.

[0252] Dragee cores are provided with suitable coatings. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added to the tablets or dragee coatings for identification or tocharacterize different combinations of active compound doses.

[0253] Pharmaceutical compositions which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffm, or liquid polyethyleneglycols. In addition, stabilizers may be added.

[0254] Dosage forms of the chemical agents of the invention may alsoinclude injecting or implanting controlled releasing devices designedspecifically for this purpose or other forms of implants modified to actadditionally in this fashion. Controlled release of an agent of theinvention may be effected by coating the same, for example, withhydrophobic polymers including acrylic resins, waxes, higher aliphaticalcohols, polylactic and polyglycolic acids and certain cellulosederivatives such as hydroxypropylmethyl cellulose. In addition,controlled release may be effected by using other polymer matrices,liposomes and/or microspheres.

[0255] Chemical agents of the invention may be provided as salts withpharmaceutically compatible counterions. Pharmaceutically compatiblesalts may be formed with many acids, including but not limited tohydrochloric, sulphuric, acetic, lactic, tartaric, malic, succinic, etc.Salts tend to be more soluble in aqueous or other protonic solvents thatare the corresponding free base forms.

[0256] For any chemical agent used in the method of the invention, thetherapeutically effective dose can be estimated initially from cellculture assays. For example, a dose can be formulated in animal modelsto achieve a circulating concentration range that includes the IC50 asdetermined in cell culture (e.g. the concentration of a test agent,which achieves a half-maximal inhibition of infection or colonization orpresence of a biological entity). Such information can be used to moreaccurately determine useful doses in humans.

[0257] Toxicity and therapeutic efficacy of such chemical agents can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g. for determining the LD50 (the dose lethal to50% of the population) and the ED50 (the dose therapeutically effectivein 50% of the population). The dose ratio between toxic and therapeuticeffects is the therapeutic index and it can be expressed as the ratioLD50/ED50. Compounds that exhibit large therapeutic indices arepreferred. The data obtained from these cell culture assays and animalstudies can be used in formulating a range of dosages for use in humans.The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED50 with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized. The exactformulation, route of administration and dosage can be chosen by theindividual physician in view of the patient's condition (see for exampleFingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch.1 p1).

[0258] Dosage amount and interval may be adjusted individually toprovide plasma levels of the active agent which are sufficient tomaintain symptom-ameliorating effects. Usual patient dosages forsystemic administration range from 1-2000 mg/day, commonly from 1-250mg/day, and typically from 10-150 mg/day. Stated in terms of patientbody weight, usual dosages range from 0.02-25 mg/kg/day, commonly from0.02-3 mg/kg/day, typically from 0.2-1.5 mg/kg/day. Stated in terms ofpatient body surface areas, usual dosages range from 0.5-1200 mg/m²/day,commonly from 0.5-150 mg/m²/day, typically from 5-100 mg/m²/day.

[0259] Alternately, one may administer the compound in a local ratherthan systemic manner, for example, via injection of the compounddirectly into a tissue, often in a depot or sustained releaseformulation. Furthermore, one may administer the drug in a targeted drugdelivery system, for example, in a liposome coated with tissue-specificantibody. The liposomes will be targeted to and taken up selectively bythe tissue. In cases of local administration or selective uptake, theeffective local concentration of the agent may not be related to plasmaconcentration.

[0260] The chemical agents of the invention can also be deliveredtopically. For topical administration, a composition containing between0.001-5% or more chemical agent is generally suitable. Regions fortopical administration include the skin surface and also mucous membranetissues of the vagina, rectum, nose, mouth, and throat. Compositions fortopical administration via the skin and mucous membranes should not giverise to signs of irritation, such as swelling or redness.

[0261] The topical composition may include a pharmaceutically acceptablecarrier adapted for topical administration. Thus, the composition maytake the form of a suspension, solution, ointment, lotion, sexuallubricant, cream, foam, aerosol, spray, suppository, implant, inhalant,tablet, capsule, dry powder, syrup, balm or lozenge, for example.Methods for preparing such compositions are well known in thepharmaceutical industry.

[0262] In one embodiment, the topical composition is administeredtopically to a subject, e.g. by the direct laying on or spreading of thecomposition on the epidermal or epithelial tissue of the subject, ortransdermally via a “patch”. Such compositions include, for example,lotions, creams, solutions, gels and solids. Suitable carriers fortopical administration preferably remain in place on the skin as acontinuous film, and resist being removed by perspiration or immersionin water. Generally, the carrier is organic in nature and capable ofhaving dispersed or dissolved therein a chemical agent of the invention.The carrier may include pharmaceutically-acceptable emolients,emulsifiers, thickening agents, solvents and the like.

[0263] The invention also features a process for separating macrocyclicditerpenes from a biomass containing same, said process comprisingcontacting the biomass with an aqueous solvent for a time and underconditions sufficient to extract the macrocyclic diterpenes into saidsolvent.

[0264] The aqueous solvent is preferably water.

[0265] Suitably, the biomass is derived from a plant, which ispreferably a member of the Euphorbiaceae family of plants or botanicalor horticultural relatives of such plants. Matter from the plant (e.g.foliage, stems, roots, seeds, bark, etc.) is preferably cut, maceratedor mulched to increase the surface area of the plant matter for aqueousextraction of the macrocyclic diterpenes.

[0266] The process preferably further comprises adsorbing themacrocyclic diterpenes to a non-ionic adsorbent, which is suitably anon-ionic porous synthetic adsorbent. Among the non-ionic poroussynthetic adsorbents that can be used for the purposes of the presentinvention include, but are not restricted to, aromatic copolymers mainlycomposed of styrene and divinylbenzene, and methacrylic copolymersmainly composed of monomethacrylate and dimethacrylate. Such non-ionicporous synthetic adsorbents which comprise, as the basic structure,aromatic copolymers mainly composed of styrene and divinylbenzeneinclude, for example, Diaion HP10, HP20, HP21, HP30, HP40, HP50, SP850,and SP205 (trade names: Mitsubishi Chemical Corp.), and Amberlite XAD-2,XAD4, (trade names: Rohm and Haas Co.). Examples of non-ionic poroussynthetic adsorbent which comprise, as the basic structure, methacryliccopolymer mainly composed of monomethacrylate and dimethacrylate areDiaion HP2MG, Amberlite XAD-7, XAD-8 and XAD-16 and others.

[0267] Preferably, the process further comprises eluting macrocyclicditerpenes from the non-ionic adsorbent with water and water-solubleorganic solvent(s).

[0268] The treatment may be conducted by a batch method using water andwater-soluble organic solvent(s) which dissolve macrocyclic diterpenes,or may also be conducted continuously or in batch using a columnchromatography method.

[0269] Examples of a water-soluble organic solvent which may be used inthe present invention are alcohols such as methanol, ethanol, n-propylalcohol, isopropyl alcohol, and tert-butanol, ethers such as dioxane andtetrahydrofuran, ketones such as acetone, amides such asdimethylformamide, sulfur-containing compounds such asdimethylsulfoxide. Two or more of such organic solvents may be mixed foruse. In addition, solvents less soluble in water, for example, alcoholssuch as n-butanol, esters such as methyl formate and methyl acetate, andketones such as methyl ethyl ketone may also be used to the extent thatit does not separate during development. Particularly preferredwater-soluble organic solvents are alcohols, in particular, methanol,ethanol, propyl alcohol, and the like. Furthermore, different kinds ofsolvent may also be used sequentially for development.

[0270] Macrocyclic diterpenes can be further purified using media andtechniques which separate compounds on the basis of molecular sizeand/or polarity. In a preferred embodiment of this type, the macrocyclicditerpenes are separated using Sephadex HL-20 resin and preferably usingwater and water-soluble organic solvent(s) for development.

[0271] The present invention is further described by the followingnon-limiting Examples.

EXAMPLE 1 PKC Activation: Kinase Activity of PKC as Measured by EnzymeAssay

[0272] Preparation of Chemicalfractions From E. peplus

[0273] Sap from E. peplus plants was collected, stored at −20° C.,thawed and stored at 4° C. for 1 week prior to use. The H fraction wasprepared from frozen sap by thin layer chromatography (TLC) as describedin International Patent Application No. PCT/AU98/00656 and was stored asdried silica-associated material at 4° C. This material was enriched injatrophanes and pepluanes. One to two months prior to use, the materialwas dissolved in ethylene glycol dimethyl ether (DME) and stored at 4°C. The concentrations were determined from the dry weight of thematerial. For PKC assays, crude sap (PEP001) and the PEP004 fraction wasether extracted twice to produce an ether-soluble fraction enriched inditerpenes, namely, ingenanes, jatrophanes and pepluanes. The remainingwater soluble fraction was also used. An ingenane fraction was preparedfrom the ether-soluble extract by TLC as described in InternationalPatent Application No. PCT/AU98/00656.

[0274] PKC Assay

[0275] The conventional and novel protein kinase C (PKC) isoforms, intheir unstimulated state, are inactive as kinases. The C1 domain ofthese PKCs contains an autoinhibitory, pseudosubstrate site that bindsto the substrate site (C4 domain) and inactivates the kinasefunctionality of the protein. Activation of PKC results from binding ofdiacylglycerol (DAG) to the C1 domain, which, via multiplephosphorylation events and conformational changes to the protein,ultimately leads to the release of PKC autoinhibition. TPA and otherrelated compounds have been shown to bind to the C1 domain of variousPKC isoforms and presumably by similar means as DAG, lead to theiractivation.

[0276] The kinase activity of rat brain PKC (Promega) was determinedusing the Peptag™ Non-Radioactive Protein Kinase Kit (Promega). Usingagarose gel electrophoresis the technique visualises the opposingelectrostatic charge of a fluorescently labeled peptide (PLSRTLSVAAK)compared to the phosphorylated version of the same peptide.

[0277] The results of an assay of PKC with the fluorescent substrate(PepTag) are shown in FIG. 1. The reaction mixture was separated by gelelectrophoresis, showing migration of the unreacted substrate (a) to theanode (top), and the product (b), which is more negatively chargedbecause of phosphorylation by PKC, moving towards the cathode (bottom).The positive control activator (phosphatidyl serine) supplied by themanufacturer (lane 2) showed strong activation compared with PKC andsubstrate alone (lane 1). Various dilutions of TPA also showedactivation of PKC (lanes 3, 4 and 5).

[0278] An ether extract of E. peplus sap, reconstituted indimethoxyethane (DME) and incubated with PKC at a final dilution of 1 in5 relative to the sap, gave a significant level of action (lane 7), asdid the crude sap itself (lane 9). In the latter case, however, both thesubstrate and product (band c, lane 9) were found further towards thecathode. This result was interpreted as being due to a carboxypeptidaseactivity in the crude sap, cleaving the C-terminal, positively-chargedlysine from the substrate peptide. This was confirmed by the findingthat the aqueous layer from ether extraction had minimal PKC-activatingability, but altered migration of the substrate in the same way as thecrude sap (lane 8). DME itself had no activity (lane 10).

[0279]FIG. 2 shows the results of testing fractionated materialssimultaneously with negative (lane 1) and positive controls (lane 2).Fraction H (mixture of jatrophanes and pepluanes) showed a low activity(lane 3), seen as a halo of product (arrow) moving away from theunreacted substrate. A similar result was found for the ingenanefraction (lane 4).

[0280] All of the E. peplus fractions are tested for activation of allthe available protein kinase enzymes using the peptide-based fluorescenttag test described above. The isoenzymes available for this experiment(Panevera) were α, β1, β11, γ, δ, ε, η and ζ.

[0281] Essentially, the kinase activity of the PKC sample was assessedbefore stimulation (Negative Control) and after stimulation with PEP001,phosphatidyl serine (an acid-lipid, known to activate PKC, provided byPromega; Positive Control) and TPA (20 μg/mL). The results presented inFIG. 3 indicate that PEP001, at dilutions of 1:125 and 1:500, activatesPKC to a similar level as phosphatidyl serine (200 μg/mL) and to agreater level than TPA (20 μg/mL). From this experiment, it is clearthat the PEP001 activates PKC.

EXAMPLE 2 PKC Activation: Translocation of PKC

[0282] Activation of PKC can also be demonstrated by a simplefluorescence microscopy-based assay. Upon activation, PKC is known totranslocate from the cytoplasm to the plasma membrane of the cell. Byfusing PKC enzymes to the green fluorescent protein (GFP) or enhancedGFP (EGFP), activation of the PKC can be detected by the movement ofdiffuse cytoplasmic GFP to a ring of fluorescence associated with theplasma membrane. Using this assay, crude E. peplus extract has beenshown to activate PKCβ and PKCγ.

[0283] MM96L cells were first transfected using a commercially-availablekit (Qiagen Effectine Transfection Kit) with a PKC-GFP expression vector(Clontech; http://www.clontech.com/gfp/) and allowed to produce thePKC-GFP protein for 24 hr. The cells were then treated with crude E.peplus extract and TPA and observed under a fluorescent microscope (488nm excitation). Two controls were used—no DNA, which allows for theidentification of non-transfected cells, and no drugs, which allows forthe calculation of transfection efficiency and the identification oftransfected cells without PKC activation. pPKCβ-EGFP and pPKCγ-EGFP weretested, and crude E. peplus extract was shown to induce movement of thefluorescence from the cytosol to the plasma membrane, indicating thatcrude E. peplus extract activated these PKC enzymes. The results areillustrated in FIGS. 4A and 4B, which respectively show expression ofPKCβ in the absence of any drug and after exposure to crude E. peplusextract for 2 hr.

[0284] In another experiment, translocation of individual PKC isoformswas observed using fluorescence microscopy and used as an indication ofactivation by PEP003 and PEP005.

[0285] Five EGFP-PKC isoforms (Clontech) were available for thisexperiment, enabling the screening of the three predominant PKC families(i.e. classical, novel and a typical PKCs). The members of the variousPKC families are α, β, and γ (classical), θ (novel) and ζ (atypical).

[0286] HeLa cells were plated out in a 24-well plate containingcoverslips and transfected with PKC isoforms fused to EGFP, using acommercially available effectine-transfection kit (QIAGEN, Pty. Ltd.).Cells were exposed to the transfection reagents for 16-24 hr.Subsequently, transfected cells were treated for one hour with TPA (100ng/mL), bryostatin-1 (5 pg/mL), PEP003 (2.25 μg/mL; 5 μM) or PEP005 (670μg/mL) 1.5 μM). Following treatment, cells were fixed on coverslips andmounted on glass slides. The slides were subsequently examined visuallyby fluorescence microscopy, photographed, and over 150 cells werecounted/treatment/PKC isoform. Counted cells were classified accordingto the localisation of the PKC-EGFP fluorescence as either cytoplasmicor plasma membrane using ImagePro™ 4.1 (FIG. 5). Several cells alsoshowed localisation to the Golgi, or similarly located cellularstructure (FIG. 5). The number of these cells was also counted. Resultsare presented as an average and standard deviation of percentages ofcells (Table 1).

[0287] The results presented in FIG. 6 show that PKC α, β and γ aretranslocated from the cytoplasm to the plasma membrane in response totreatment with PEP003, PEP005 and TPA but not with bryostatin-1. Asexpected, the diacylglycerol-independent PKCζ is not translocated inresponse to any treatment. PKCθ is translocated in response to PEP003,TPA and bryostatin-1, however, PEP005 does not induce any change in theisoenzymes localization. The results also show that treatment of PKCαand γ transfected cells with TPA, PEP003 and PEP005 leads to an increasein the number of cells displaying Golgi-like fluorescence. PKCβtransfected HeLa cells treated with TPA also show an increase inGolgi-like fluorescence. In contrast, treatment with PEP005 andbryostatin-1 decreases the number of cells with PKCβ concentrated in theGolgi. The number of PKCθ transfected HeLa cells with Golgi-likelocalization is increased in response to all treatments.

[0288] The above results indicate that PEP003 and PEP005 inducetranslocation of the classical and novel PKC isoforms tested, suggestingthat these compounds activate members of the classical and novel PKCfamilies. TPA, Bryostatin-1, PEP003 and PEP005 fail to inducetranslocation of PKCζ, suggesting that PEP003 and PEP005 do not activatemembers of the a typical PKC family. Furthermore, TPA, Bryostatin-1,PEP003 and PEP005 display differences in their ability to inducetranslocation of the specific PKC isoforms to the plasma membrane and/orGolgi. These differences may play a role in determining the differentbiological actions of these compounds.

EXAMPLE 3 Binding of Compounds to PKC

[0289] A competition assay was performed to determine whether thediterpene esters of the instant invention bind to the phorbol esterbinding site of PKC. This competition assay showed that 23 μg/mL PEP003displaced >90% [3H]-phorbol dibutyrate from binding to rat brainhomogenate, used as a source of PKC (Gonzalez et al., 1999). Thisbinding was not blocked by co-incubation with bisindolylmaleimide. Theseresults show that PEP003 binds to the phorbol ester binding site of PKC,and bisindolylmaleimide does not.

EXAMPLE 4 Activation of Latent HIV Infection

[0290] The use of highly active anti-retroviral therapy such ascombinations of reverse transcriptase inhibitors and protease inhibitors(HAART) has significantly prolonged the life of individuals infectedwith HIV. However, the regimen is very burdensome, requiring strictadherence to prevent a recurrence of viraemia. Long-lived cells capableof actively transcribing virus, such as CD⁴⁺ cells, act as a majorlatent reservoir and enable the virus to avoid anti-retroviralchemotherapy or immune system surveillance. There is, therefore, anurgent need to find an agent which activates latent virus from theinfected cells. Activated virus could then be killed by aggressiveanti-retroviral chemotherapy and it has been hypothesized that immunesystem surveillance could also be improved under these conditions. Suchan agent could have utility in other disease states in which virus issequestered in infected cells, e.g. herpes infections. Anti-canceragents have been widely investigated as potential anti-HIV agents.Several PKC activators have been shown to activate latent retroviruses.For example, PMA has been shown to activate latent HIV in monocytes(Tobiume et al., 1998). However, PMA is a known tumor promoter.

[0291] A latently HIV-1 infected cell line (U1), derived from thepromonocytic cell line U937 after infection with HIV-1 LAI strain, wasused in these experiments. In the absence of activation, no or littlevirus (measured as p24 production) is produced by the U1 cell line.Phorbol esters are known to activate virus production from these cells(Tobiume et al., 1998) and so TPA/PMA was used as a positive control inthese experiments.

[0292] U1 cells were cultured in RPM 1-1640 medium supplemented with 10%fetal bovine serum, 10⁵ cells/mL were cultured for 20 hr in the presenceand absence of various concentrations of either the phorbol ester TPA orcrude E. peplus sap (PEP001) or PEP004 (H1) derived therefrom.Supernatants were collected and viral replication monitored bydetermination of the amounts of HIV p24 gag protein in the culturesupernatants by ELISA, using a NEN Life Science HIV-1 p24 ELISA kit. p24values were calculated from OD values using a standard curve.

[0293] TPA, the crude sap (PEP001) from E. peplus and the PEP004fraction all activated HIV from U1 cells, as illustrated in FIG. 7. Thecrude sap (PEP001) was 50 times less active than TPA. The PEP004fraction was 1000 times less active than TPA.

EXAMPLE 5 Lytic HIV Activity Inhibited by PEP003 and PEP004

[0294] The human immunodeficiency virus (HIV), a retrovirus, is thecause of the fourth greatest killing disease in the world, infectingmore than 36 million people. A number of anti-retroviral compounds havebeen approved for clinical use, but many HIV strains have developedresistance to these drugs. There is clear and immediate need for newanti-retroviral compounds.

[0295] Experiments were conducted to assess the effect of the compoundsof the instant invention on HIV-1 replication in acutely infected Tcells. Peripheral blood mononuclear cells (PBMC) were obtained fromnon-HIV-1, non-HIV-2, non-Hepatitis B/C infected donors, stimulated withphytohemagglutinin-M and grown in culture media supplemented with 10U/mL interleukin-2. The activated PBMC were infected with 10 g (LowTitre) and 100 ng (High Titre) of CA-p24 equivalents of the HIV-strainpNL4-3. Cells were infected for two hr after which, the virus wasremoved and the cells were washed with culture media. Equivalent numbersof cells were seeded into 24 well plates and compounds were added to thecultured cells that included: TPA at 8 nM and 80 nM, Ingenol at 280 nM,PEP003 at 500 nM, 50 nM and 5 nM, or PEP004 at dilutions of 1×10⁴ and1×10⁵ from the stock (final concentrations). In addition, uninfectedactivated PBMC were grown in the presence of TPA (80 nM), Ingenol (280nM), PEP003 (500 nM) and PEP004 (1×10⁴ dilution). Other cultures wereneither infected nor treated with any compound, or infected but nottreated with any compound. Supernatant was removed from each culture atday 0, 3, 7, and 10. The amount of HIV-1 CA-p24 was determined using acommercially available ELISA assay. Three independent experiments wereperformed.

[0296] The data presented in FIGS. 8A-8D show that PEP003 reduced virusreplication kinetics in a dose-dependent manner. PEP003 atconcentrations of 500 nM, 50 nM and 5 nM reduced the replication rate byapproximately 99.9%, 95% and 47%, respectively, relative to theuntreated, infected cells. PEP004 at dilutions of 1×10 ⁴ and 1×10⁵reduced the replication rate by approximately 66% and 15%, respectively.Viral load seemed to alter these results slightly, as higher initialinoculums of virus reduced the total inhibition of PEP003 at 500 nM or50 nM to approximately 97% (t-test; p<0.001) or 88% (t-test; p<0.074),respectively. The control compounds Ingenol (2.8 μM) and TPA (80 nM or 8nM) reduced HIV-1 replication rates by approximately 35%, 98% and 38%,respectively.

EXAMPLE 6 Enhancement of the Cytomegalovirus Promoter Activity as aMethod for Improving Gene Therapy

[0297] Viruses and viral promoters especially adenovirus and CMV areused to deliver gene therapy in a range of human disease conditions.Gene expression and, hence, therapeutic effect will be enhanced if thepromoters driving their transcription can be activated further by anagent.

[0298] Human melanoma cells were infected with ten-fold dilutions ofadenovirus 5 in culture, treated with dilutions of PEP005, PEP006,PEP008 and PEP010 and adenovirus replication determined 2 days later byimmunhistochemical detection of virus-replicating cells. Virusreplication (enumerated as the number of stained cells followingsuccessive incubations with adenovirus antibody, peroxidase-conjugatedprotein A and peroxidase substrate) was increased by 344% with 67 ng/mLPEP005, 256% with 295 ng/mL PEP006, 248% with 226 ng/mL PEP008 and 147%with 67.5 ng/mL PEP010.

[0299] The CMV promoter is commonly used to activate the transcriptionof genes in constructs transfected into a variety of cells, due to itsstrong transcriptional activity in a variety of human cell types. Theability of TPA to increase this activity has been demonstrated in cellsundergoing non-productive infection with an adenovirus construct(Christenson et al., 1999), thus raising the possibility of increasingthe production of a therapeutic protein encoded by a similar construct.

[0300] Human melanoma cells (MM96L; 50,000 per microtiter well) weretreated with TPA or dilutions of crude E. peplus sap, infected with a1/20 dilution of a pool of adenovirus-5 expressing β-galactosidasedriven by the CMV promoter. After incubation for 20 hr, the wells werewashed with 3×with PBS, 50 μL of chlorophenol red galactoside (GPRG)substrate solution added and the absorbance at 540 nm read after 90 min.The inventors found TPA (100 ng/mL) and crude E. peplus sap (diluted 1in 10,000) both induced the CMV promoter activity by >3-fold.

EXAMPLE 7 Activation of Innate Immune Responses: Induction of NeutrophilInvasion in Skin

[0301] Neutrophils represent about 70% of peripheral white blood cellsin humans and play a pivotal role in inflammation and the innate defenseagainst disease (Mollinedo, 1999). Upon activation, neutrophils releasesuperoxide radicals and granules containing a variety of enzymes andother compounds. These secretions are able to destroy invadingpathogens, but also result in inflammation and associated tissue damage.

[0302] The inventors found that E. peplus sap causes accumulation ofneutrophils at the site of application, showing that E. peplus sap iscapable of recruiting neutrophils. A mixture of active diterpenesobtained as an ether extract from E. peplus sap was applied (2 μL of 100mg/mL in ethanol) on the skin of a nu/nu mouse. After 24 hr, the animalwas sacrificed and the skin fixed in 10% formalin for sectioning andhematoxylin/eosin staining. As shown in FIGS. 9A and 9B, control skinshowed normal skin structure with few infiltrating monocytes. Thetreated skin showed large numbers of infiltrating neutrophils,characterized by their polymorphic nuclei. There was no evidence ofgross damage to the skin.

EXAMPLE 8 Neutrophil Infiltration Activity

[0303] Basal cell carcinoma (BCC) is the most common cancer in theCaucasian population, with the highest annual incidence globally havingbeen recorded in Australia (Miller et al., 1994, Marks et al., 1993).New developments have begun looking at treating non-melanoma skin cancer(NMSC) using topical therapies. The essence of this therapy may relyupon the induction of an inflammatory response with infiltration ofleucocytes, in particular neutrophils.

[0304] To assess whether the compounds of the invention induceneutrophil infiltration, an experiment was designed on C57BL/6J mice.Twenty-four mice were divided into six groups of four mice per group. Inthree of these groups the mice had a B16 melanoma injected s.c. (2 sitesper mouse, 5×10⁵ cells/site), that was left to grow for 8 days toapproximate tumor sizes of 5-8 mm in diameter. A single application ofone of all three compounds was then applied to the tumor or to normalskin. Each compound was applied on two groups of mice, one with tumorand 1 without tumor. The three compounds were PEP010 (2 μL; 150 mM) in10 μL of isopropanol gel (isopropyl alcohol 25% (w/w), propyl alcohol25% (w/w)) (vehicle), PEP009 (2 μL of stock) in 10 μL of vehicle orvehicle alone as a control. One mouse from each group was thensacrificed at either 4 hr, 24 hr, 48 hr or 144 hr post singleapplication of compound and then tissue excised and sections preparedfor histology.

[0305] The results at 4 hr show only minimal response with 1+ patchyneutrophils for both PEP010 on B16 tumor and PEP009 on normal skin and2+ neutrophils present for PEP009 on B16 tumor (Table 2). At 24 hr,there are no neutrophils present in the control groups with vehiclealone but a 4+ neutrophil infiltration with PEP010 and PEP009application, on both tumor and normal skin (FIGS. 10A and 10B). Inaddition, 60-85% of the superficial tumor cells were apoptotic ornecrotic in the B 16 groups. At 48 hr, there was a similar pattern witha 4+ neutrophil presence with PEP010 and PEP009 application while thecontrol groups showed an absence of neutrophils (FIGS. 10A and 10B).Along with the tumor cell necrosis and apoptosis, there is also evidenceof some neutrophil breakdown at the 48 hour interval. The 144 hour groupshowed a lack of neutrophils in the control group and a presence of 2-4+neutrophils, which were mostly now degenerate in the PEP010 and PEP009groups. There was extensive necrosis of tumor and skin, and clear signsof granulation tissue and early repair.

[0306] This study shows that the PEP010 and PEP009 induce a markedinflammatory infiltrate of neutrophils as compared to vehicle alone andthis influx of polymorphonuclear cells may be significant in alteringthe growth of certain skin cancers.

EXAMPLE 9 Activation of Innate Immune Responses: Induction of aRespiratory Burst in Peripheral Blood Mononuclear Cells

[0307] Monocytes/macrophages are blood-borne and tissue cells which areusually activated by T lymphocytes and antibodies. Upon activation, theyare able to phagocytose pathogens, release superoxide radicals and arean important source of cytokines. Crude E. peplus extract was shown tobe able to induce the release of superoxide radicals by use of afluorescence-activated cell sorting (FACS)-based method, in whichsuperoxide radicals are detected by the dye dihydroethidium. Inaddition, phagocytic activity was activated by E. peplus, as shown byincreased uptake of nitroblue tetrazolium and adherence to plastic wasincreased by E. peplus; this is believed to indicate activation anddifferentiation of macrophages.

[0308] Human peripheral blood mononuclear cells (PBMC) prepared bystandard Ficoll separation comprise approximately 5% monocytes. PBMCwere incubated with dihydroethidium, a reduced form of the dye whichbecomes fluorescent when oxidized by a respiratory burst, then treatedin 10% FCS-RPMI 1640 at 37° C. for 15 min with crude E. peplus extractdiluted {fraction (1/1000)} or 100 ng/mL TPA and analyzed by flowcytometry using conventional methods (Handbook of Flow CytometryMethods, p. 151). The mean channel numbers for fluorescence were 618(controls) and 818 (E. peplus extract diluted {fraction (1/1000)}).These results, illustrated in FIGS. 11A and 11B, show that the E. peplusextract induced intracellular oxidation of the dye, typical of arespiratory burst. Phagocytic activity was determined by a conventionalmethod (Hudson and Hay, Practical Immunology, 3^(rd) edition, p. 74).Cells were treated in 10% FCS-RPMI 1640 at 37° C. for 20 min withintroblue tetrazolium (NBT) and crude E. peplus extract (PEP001) diluted{fraction (1/1000)} or 100 ng/mL TPA, followd by counting the number ofblue-stained cells in a haemocytometer. The average of three fields gavefigures of <2% (controls), 10% (TPA) and 8.7% (E. peplus sap) cellsstained blue. This demonstrates induction of phagocytic activity, partof the normal response to infectious agents, by E. peplus sap, as shownby uptake by cells of the blue NBT precipitate.

[0309] Experiments were also carried out using 2′,7′-dichlorofluoresceindiacetate (DCFH-DA) to measure the production of H₂O₂.(J P Robinson,Oxidative burst methods, in Handbook of Flow Cytometry Methods,Wiley-Liss Inc, pp147-149, 1993). H₂O₂ oxidizes the non-fluorescentprobe (DCFH-DA) to a fluorescent probe that can then be detected by aflow cytometer. Peripheral blood mononuclear cells (PBMC) were extractedfrom a donor blood sample by lysis of heparinized blood and used in asuspension of 1×10⁶/mL of phosphate buffer, pH 7.3. The cells were thenincubated, with DCFH-DA (1 μL/mL of 20 mM stock) for 15 minutes to allowit to be taken up and trapped by hydrolysis with cellular esterases. Thecells were then stimulated by test compounds for 15 min at 37° C.Controls included in the experiment were unloaded control (cells with noDCFH-DA) and loaded control (cells with DCFH-DA, but no stimulation).These were used to monitor the non-specific oxidation of unstimulatedcells. The cells were then analyzed on the flow cytometer (excitation at488 nm, emission at 525±20 nm), gating each sample for individual cellpopulations—granulocytes, monocytes and lymphocytes (Table 3).

[0310] All compounds except Bryostatin induced a respiratory burst, theeffect being strongest in granulocytes and monocytes compared withlymphocytes. Similar results were obtained by measuring the reduction,under the same conditions, of nitroblue tetrazolium, measured as theproportion of purple-stained cells counted under the microscope.

[0311] Evidence for the requirement of PKC activation was obtained byaddition of bisindolylmaleimide (10 μg/mL or 1 μg/mL) at the same timeas PEP005, PEP006, PEP008 and PEP010. This PKC inhibitor blocked therespiratory burst seen with TPA and PEP003.

[0312] Phagocytosis with Fluorescent Beads

[0313] Phagocytosis by peripheral blood mononuclear cells (PBMCs) wasassayed (Steinkamp et al., 1982) using 1 μm Fluoresbrite™ yellow-greenfluorescent latex spheres (Polysciences, Inc., Warrington, Pa.). Asample of whole, heparinized blood was treated with drug and 5×10E7fluorescent latex beads in 10 mL of PBS added per mL of suspension.Cells were incubated and maintained in suspension for 30 min by means ofa shaker platform at 37° C. The stimulated and non-stimulated sampleswere then lysed to isolate PBMCs. The PBMCs were run on the flowcytometer measuring FITC (excitation at 488 nm, emission at 525±20 nm),gated for fluorescence (phagocytosed spheres) and light scatter (cellsize).

[0314] The data presented in Table 4 indicate that TPA, PEP006, PEP008,PEP003 and PEP005 all stimulate phagocytosis in PBMCs.

EXAMPLE 10 Activation of Innate Antiviral Activity

[0315] Many viruses, including alphaviruses, are sensitive to innateantiviral activities, which are often mediated by the activation ofinterferon α/β responses (Antalis et al., 1998). Such antiviralactivities inhibit the ability of cells to support viral replication.For many viral infections, including those caused by Ross River virus,viral replication results in virus-induced cytophathic effect (CPE) orcell death. Treatrnent of human fibroblast cells with E. peplusingenanes was shown to activate antiviral activity and prevented CPEinduced by an alphavirus infection.

[0316] Human skin fibroblasts (10e4/well) were seeded in 96 well plateand left overnight to adhere. An extract of E. peplus ingenanes wasadded at 5 μg/mL for 48 hr. An alphavirus (Ross River virus, T48) wasthen added at a dose of 1, 10 and 100 cell culture ID50 for 6 days (LaLinn et al., 1996). The cytopathic effect of the viral infection wasassayed using crystal violet staining. Protected cells stain violet,whereas cells which have suffered CPE detach from the plate, leaving thewell unstained. Alphavirus-induced CPE was observed in treated cellsonly at a 100-fold greater dose of virus than was required to induce CPEin untreated cells, indicating that a significant degree of protectionwas conferred by the E. peplus extract.

EXAMPLE 11 Protection Against Intra-Peritoneal Streptococcal Infection:Effect of PEP003 and PEP004 on Systemic Group A Streptococcal Infectionin Mice

[0317] Infection of humans with group A streptococcus (Streptococcuspyogenes) (GAS) can cause a variety of clinical manifestations includingthe relatively minor pharyngitis (“trep throat” and impetigo(superficial skin infection) to more severe invasive infections such astoxic shock syndrome and necrotizing fasciitis, both of which, may leadto multisystem organ failure. Lastly, the GAS post-infectious sequelaeof rheumatic fever (RF), rheumatic heart disease (RHD) and acuteglomerulonephritis (AGN) are a major problem in developing countries andindigenous populations, particularly in Australian Aboriginals. Currenttreatment for controlling GAS infection is with antibiotic therapy,however, since continual high dose administration of antibiotic isrequired in cases of repeated episodes of acute RF and the developmentof RHD, poor compliance is often associated with the persistence ofthese GAS-associated diseases. The development of a vaccine against GASinfection would prevent GAS-associated diseases including RF and RHD. Inthe absence of a vaccine, however, the development of new drugs withimproved anti-bacterial activity may provide promising therapeuticagents.

[0318] The inventors' aim was to test the ability of the PEP003 andPEP004 to systemically protect against GAS infection, in vivo. Mice(n=10) were treated with 50 μL of PEP003 (500 nM), PEP004 (1:100dilution from stock) or control (PBS/10% acetone), 24 hr prior to andthereafter i.p. challenge with live GAS. Two different strains of mice(Quackenbush and B10.BR) and four different GAS strains (NS-1, PL-1,88/30 and M1) were used. Mice were monitored for two weekspost-challenge and the percentage survival of mice determined.Percentage survival in Quackenbush mice challenged with PL-1 GAS was 70%(PEP003), 60% (PEP004) and 40% (control) (Table 5). Control mice thathad been given the same successive treatment of PEP003 and PEP004 (butnot challenged) to rule out any potential adverse side effects of thecompounds were then also challenged with PL-1; survival was 40%, 80%,and 20% for PEP003, PEP004 and controls, respectively (Table 6). In thelatter experiment, the protective effect of PEP004 approachedsignificance (p=0.06), however, small numbers of mice were used (n=5).In Quackenbush mice challenged with NS-1 GAS, survival was 50% forPEP003 and controls, and 80% for PEP004 (Table 5). In B10.BR micechallenged with M1 GAS, survival was 10% for controls, 30% for PEP003and 0% for PEP004 (Table 5). In B10.BR mice challenged with 88/30 GAS,survival was 20% for controls, 30% for PEP004 and 0% for PEP003 (Table5). The data indicate a possible protective effect of PEP004 againstsystemic GAS challenge in Quackenbush mice. In addition, these dataindicate that a weekly treatment regimen of PEP003 and PEP004 prior toGAS challenge may be more effective.

EXAMPLE 12 Anti-Escherichia coli Activity of PEP003: Activation ofLeucocytes

[0319] Blood was collected into a Sodium Heparin tube (Becton DickinsonVACUTAINER) and leucocytes prepared by lysis of red blood cells(Handbook of Flow Cytometry Methods. Robinson J P. Wiley-Liss Inc 1993.Oxidative Burst Methods H₂O₂ DCF Assay by Flow cytometry p 147-149).Leucocytes were resuspended and divided equally into two tubes such thateach tube contained 7×10⁶ peripheral blood cells (PBCs). Both tubes werethen centrifuged (Beckman, GS-6) at 1000 rpm for 10 minutes. Thesupernatant was removed and the volume was then adjusted to 1 mL withRPMI 1640 (Gibco BRL, antibiotic free supplemented with 10% v/v fetalbovine serum. 100 μL of PEP003 (to give a final concentration of 23μg/mL containing 10% acetone was then added to one tube and to theother, 100 μL of PBS/10% Acetone. To each tube, 10 μL E.coli (competentcells, XL10-Blue, Stratagene) was also added (to give a ˜{fraction(1/100)} dilution of a static culture). Both tubes were vortexed thencentrifuged (Beckman, GS-6) at 2500 rpm for 10 minutes. Lids wereloosened and the tubes were incubated at 37° C./5% CO₂. Following 16 hrincubation, the tubes were vortexed. To estimate the number of E. coli,50 mL was taken from both tubes as well as the static starter culture(stored at 4° C.), transferred to Eppendorf tubes and centrifuged(Beckman, GS-15R) at 10,000 rpm for 10 minutes. Supernatant (˜45 μL) wasremoved and the pellet resuspended in the remaining ˜5 μL. A smear wasmade on a glass slide using the 5 μL bacterial suspension and stainedusing Quick Dip (Histo.Labs, Riverstone, Australia), a modified methodof the Wright-Giemsa stain, which stains bacteria blue. E. coli werecounted using a conventional light microscope (×400) with an eyepiecemicrometer (100 μm×100 μm). This count was then adjusted to give a totalcount in the smear (area =12.5×10⁵ μm²) and expressed as the number ofE. coli per mL. Another method of measuring growth of E. coli was toread the absorbance (595 nm) of the supernatant.

[0320] The results presented in FIGS. 12 and 13 show that treatment ofleucocytes with PEP003 results in a significant reduction in bacterialnumbers.

EXAMPLE 13 Treatment of Ringworm

[0321] Ringworm is a subcutaneous mycosis or dermatophytosis caused byfungi of the species Trichophyton, Microsporum and Epidermophyton, inwhich the infection is confined to the keratinous structures of thebody. A two week old ringworm lesion, determined to be Trichophytonmentagrophytes var. mentagrophytes by culture, on the volar surface ofthe forearm of an adult male human was treated with a single topicalapplication of crude E. peplus extract and was shown to resolve afterseven days. Resolution of such lesions in the absence of treatment doesoccur, but is considered extremely rare.

EXAMPLE 14 Treatment for Bites if Blood-Sucking Insects

[0322] The bites of blood sucking insects such as mosquitos and sandflies often cause an itchy inflammatory reaction at the site of thebite. Although the extract mechanism of this reaction is poorlyunderstood, mast cells and histamine release are likely components ofthis reaction (Greaves and Wall, 1996; Horsmanheimo et al., 1996).

[0323] In preliminary experiments, the inventors treated human sand flybites with E. peplus extract and found a rapid reduction in the itchysensation compared to untreated bits at a distant site. Without wishingto be bound by any proposed mechanism, the inventors believe that the E.peplus extract may strongly stimulate mast cell exocytosis and histaminerelease and thereby prevent the slow release over time of thesecompounds, a feature associated with itchiness.

EXAMPLE 15 Promoter Activation as a Means of Therapy: Effect of PEP003and PEP004 on Activation of EBV Infected Cell Lines and EBV PositiveBurkitt's Lymphoma Cell Lines

[0324] Initially the effect of PEP003 and PEP004 was tested on the B95-8cell line (an EBV positive marmoset cell line that is used worldwide asone of the best EBV producers). This cell line was treated with each ofthese compounds (at different concentrations) for 3 days and 7 days,respectively, and activation of EBV virus production was measured by theappearance of a viral capsid antigen (VCA) on western blots. Also, as acomparison, EBV was activated in this cell line with TPA.

[0325] To ensure that equal amounts of each sample were analyzed, thegels were stained with Coomassie blue and the loadings were adjusted tomake them equal. Analyses of VCA in each of the samples showed that bothPEP003 and PEP004 were capable of activating EBV (at all of theconcentrations used) to similar levels as using 65 nM TPA (FIG. 14).Next the PEP003 and PEP004 were assayed on two Burkitt's lymphoma celllines and an LCL. This time only concentrations of 10⁻⁵ and 10⁻⁷ wereused. Neither PEP003 and PEP004 had much effect on the LCL (this LCLproduces some VCA without and chemical induction and this was notincreased by these compounds). PEP004 had no effect on VCA production inany of the cell lines used. However, PEP003 did induce high levels ofVCA in both Burkitt's lymphoma cell lines (Mutul and BL74), but only at10⁵ concentration (FIG. 15). Similar results were obtained when the celllines were assayed for induction of BZLF1, the initial transactivator ofEBV replication (FIG. 16). The results show that PEP003 was capable ofactivating EBV in Burkitt's lymphoma cell lines, but appeared to havelittle effect on LCLs.

[0326] In conclusion, (1) both TPA and PEP003 can modulate geneexpression in EBV transformed tumor cells at the doses used; (2) whilePEP003 induced VCA in MutuI cells TPA did not, indicating differentmodes of action; (3) surprisingly, there was no apparent effect ofPEP003 on lymphoblastoid cells, indicating potential for activatinglatent herpesvirus in tumors without affecting the normal infection.

EXAMPLE 16 Investigation into the Effect of PEP003 on the Ability ofMelanoma Cells to Stimulate NK Activity

[0327] Melanomas and other cancers can be killed by both specific (Tcell-mediated) and non-specific (natural killer cell and othermechanisms) arms of the immune response. These killer cells can begenerated in vitro by stimulating peripheral blood T cells from selectedmelanoma patients with melanoma cells derived from the same patient(“autologous”). Natural killer cells can be recognized by their lysis ofthe natural killer-sensitive cell line K562. It has been theorized thatsome anti-tumor agents alter the susceptibility of melanomas to immuneresponses.

[0328] Peripheral blood lymphocytes from patient A02, who has a strongspecific T cell response to her own melanoma cells (A02-M), were thawedand stimulated by irradiated A02-M pre-treated overnight at 37° C. with(a) PEP003 (2.25 μg/mL; 50 μM); (b) TPA (100 ng/mL); or (c) controlsolvent/buffer, and washed ×2 before addition to responding lymphocytes(washing ×2 achieves a residual agent dilution of ×100,000). After 10days of culture, the stimulated cells were harvested and used aseffectors against an NK-sensitive cell line (K562) to test for the levelof NK activity generated in culture. All determinations were performedin triplicate, at E:T ratios of 45, 15, 5 and 1.7:1. A standard 5 hour⁵¹Cr release assay was performed. Stimulations were performed in 10%fetal bovine serum/RPMI-1640.

[0329] The results presented in Table 7 and FIG. 17 indicate thatpre-treatment of melanoma cells with PEP003 significantly increases thelysis of K562 compared to both TPA and the control treatment at the E:Tratio of 45:1 (P<0.01 in both cases), suggesting that PEP003 increasesNK activity in A02 cultures.

EXAMPLE 17 Methods for Obtaining a Low-Chlorophyll, Hydrophobic FractionFrom E. peplus and Other Plant Species

[0330] Standard methods for the isolation of hydrophobic compounds fromplants involve alcoholic extraction of the whole plant. This produces anextract containing chlorophyll and other hydrophobic substances from theleaves that interfere with subsequent purification of compounds bysolvent extractions and chromatography. This is a particular problem inisolating highly bioactive diterpenes from members of the Euphorbiaceaefamily, due to co-migration with chlorophyll on silica gelchromatography. Two methods, both of which can be scaled up foreconomical, commercial production, have been developed to overcome thisproblem, as described in the present Example and in Example 18.

[0331] Fresh E. peplus plants (17 kg) were chopped and soaked in 150litres of water at 4° C. for 20 hr. The water was pumped through 50 and100 mesh sieves, filtered through 5 and 2 micron filters and thenrecirculated through a 100 mm diameter column of Amberlite XAD-16 (1.5kg, conditioned successively with ethyl acetate, methanol and water) at4° C. (approximately 1.2 L/min) for 72 hr. Adsorption of bioactivity tothe resin was found to be virtually complete within 20 hr.

[0332] The resin was then washed successively with water and 50%methanol, then eluted with 1L of methanol, followed by 2×1 L acetone.The eluates were evaporated and combined to give approximately 7 g of athick oil. This was shown by HPTLC to be substantially free ofchlorophyll and to contain the desired ingenane esters which were thenpurified as described below.

[0333] The ability to extract diterpene esters from chopped plants inwater was surprising given their relative hydrophobicity and waterinsolubility. A variety of manual (cutting with scissors) and mechanical(rotary cutters, motor-driven mulcher) plant maceration methods weresuccessful, as was extraction at room temperature. Adsorption to theXAD-16 could be achieved by stirring the resin with the filtered orunfiltered water extract and then pouring off the latter. Filtrationcould also be carried out with minimal loss of bioactivity usingdiatomaceous earth, or membrane filters (220-650 microns). XAD-7 andXAD-4 were as effective as XAD-16.

[0334] The hydrophobic adsorbent polyamide (ICN Biomedical ResearchProducts) was also used to trap the diterpenes from water; it had theadvantage of allowing the diterpene esters to be selectively eluted with50-80% methanol, thus separating them from inactive, hydrophobiccompounds, which remained on the column.

EXAMPLE 18 Method for Separation of Ingenane Esters From OtherDiterpenes

[0335] The following method is based upon the surprising discovery thatthe stems of E. peplus contain approximately 90% of the bioactivediterpenes and significantly less chlorophyll compared with the leaves.

[0336] The plants are dried in air, shaken to remove the leaves and thestems compressed and covered with an equal weight of methanol for 24 hr.The solvent is then poured off, evaporated to dryness under reducedpressure and the residue dissolved in methanol for chromatography onSephadex HL20 as described below. This method is also suitable forisolation of low-chlorophyll fractions from other plant species.

[0337] A solution of crude methanol extract from E. peplus in 4 mL 90%ethanol was loaded onto a 25 mm×1000 mm column and eluted with 90%methanol. Fractions (4 mL) were analysed by HPTLC (silica gel, developedwith 4:1 toluene: acetone and heated with phosphoric acid at 110 degreesfor 15 min). Typically, fractions 54-63 contained jatrophane andpepluane esters and fractions 64-77 the ingenane esters, thus achievingsatisfactory separation. Bioactivity, as judged by induction of bipolarmorphology in the human melanoma cell line MM96L, was retained, as forexample disclosed in PCT/AU98/00656.

[0338] This separation was surprising because the polarity of theingenane esters as judged by HPTLC on silica completely overlapped therange shown by the jatrophane and pepluane esters.

EXAMPLE 19 Process for the Purification of Diterpene Esters From E.peplus

[0339] Crude extracts obtained by the methods according to Examples 17or 18 above, or by ether extraction of latex, were fractionated bySephadex HL-20 chromatography (as above). Appropriate fractions from thelatter were combined, the methanol evaporated under reduced pressure andthe remaining water removed by freeze-drying or by ether extraction.This sample (200 μL of 100 mg/mL in methanol per injection) wasfractionated by HPLC on a Phenomenex Luna 250×10 mm C18 column with aPhenomenex guard column in 70-100% methanol at 2 mL/min, with detectionat 230 nm. Jatrophane and pepluane esters appeared at 25-42 min, PEP005at 42-44 min, PEP008 at 46-50 min, and PEP006 at 50-54 min. Similartypes of separation have been obtained by HPLC on C3 and C8 columns.

[0340] Fractions pooled from repeated runs were evaporated to dryness(rotary evaporater or freeze dryer), and stored in acetone at −20° C.under argon or nitrogen.

EXAMPLE 20 Activation of Leukocytes by Diterpene Esters, for SelectiveKilling of Human Tumor Cells in Culture

[0341] Leukocytes obtained by lysis of human peripheral blood were addedto 5000 MM96L human melanoma cells or 7000 neonatal foreskin fibroblastsper microtitre well at effector: target ratios of 1000, 100 and 10:1.Ing9 (60 ng/mL) was added and after 48 hr incubation the cultures werewashed and labelled with [3H]-thymidine for 2 hr. At 100:1 ratio ofeffector:target cells, the melanoma cells showed 9% survival with PEP008whereas the normal fibroblasts had 100% survival. Untreated leukocyteshad no effect on cell survival.

[0342] These results indicate that the diterpene esters of the inventionactivate human peripheral blood leukocytes to produce, in aPKC-dependent manner, phagocytosis and a respiratory burst which arepotentially lethal to micro-organisms and other cells.

[0343] This example shows that drug-activated, PKC-dependent processescan direct tumor-specific killing by cells of the innate immune system.

EXAMPLE 21 Pretreatment of Human Tumor Cells in Culture with DiterpeneEsters Potentiates Selective Killing by Untreated Leukocytes

[0344] The question of whether drug treatment of the target tumor cellscauses them to become susceptible to effector cells of the immune systemwas addressed as follows.

[0345] Leukocytes obtained by lysis of human peripheral blood were addedto 5000 MM96L human melanoma cells or 7000 neonatal foreskin fibroblastsper microtitre well at effector: target ratios of 1000, 100 and 10:1.The target cells had been treated with 60 ng/mL PEP008 for 20 hrbeforehand, and washed and the medium replaced before the leukocyteswere added. After 48 hr incubation with the leukocytes the cultures werewashed and labelled with [3H]-thymidine for 2 hr. At 100:1 ratio ofeffector:target cells, the melanoma cells showed 12% survival withPEP008 whereas the normal fibroblasts had 100% survival. Untreatedleukocytes had no effect on cell survival.

[0346] This result showed that the drugs also act by making tumor cellsspecifically sensitive to lysis by the immune system.

EXAMPLE 22 Topical Composition A for the Treatment of ConditionsAffecting Skin (e.g. Infections, Skin Cancers)

[0347] Tinctures: Compounds of the invention were diluted into, acetone,ethanol or isopropanol to the same final bioactivity as the E. pepluslatex as measured by bipolar activity in MM96L human melanoma cells (10million bp units per niL). Samples (2-5 μL) were applied daily for 3days to the surface of mouse melanoma B16 tumor 3-5 days afterimplanting s.c. 1 million cells on the flanks of nude mice. Efficacy,defined as 67% or more sites cured, was obtained for E. peplus sap,PEP005, PEP008 and a mixture of PEP005, PEP006 and PEP008.

EXAMPLE 23 Topical Composition B for the Treatment of ConditionsAffecting Skin (e.g. Infections, Skin Cancers)

[0348] Creams and gels: A variety of hydrophobic cream bases was foundto be ineffective when used to deliver compounds to the skin asdescribed above for the tinctures. Efficacy was obtained with the use ofan isopropanol gel, formulated as described for the tinctures.

[0349] The results show that E. peplus sap and its terpenoid componentsactivate PKC, with consequent potential to induce a wide range ofcellular responses without the high tumor promoting activity of TPA. Thecarboxypeptidase activity may have application in enhancement of tissuepenetration and in antigen processing for optimal immune responses.

[0350] Overall, the results indicate that E. peplus extract induces aset of cellular responses with affects PKC, cell cycle genes andinflammatory mediators, some but by no means all of which are similar tothe action of TPA. In particular, the results indicate that E. peplussap and its terpenoid components are useful in the treatment of avariety of infections and as adjuvants for stimulating immune responses.

EXAMPLE 24 Effect of Saps Derivedfrom Other Members of the EuphorbiaceaeFamily on MM96L Cells

[0351] Sap was collected from Synadenium grantii, Synadenium compactum,Mondenium lugardae, Mondenium guentheri, Endadenium gossweileni, and E.peplus and serially diluted ten-fold up to 10⁻⁷ into sterile 1.5 mLEppendorf™ tubes using growth medium. Ten-microlitre aliquots of eachdilution, in the presence or absence of the PKC inhibitorbisindolylmaleimide (1 μg/mL or 10 μg/mL), were added to 5000 MM96Lcells per well of a microtitre plate. After 3 days, cells were examinedfor cytotoxicity or differentiation to a bipolar dendritic phenotype.

[0352] The results presented in Table 8 show that the saps of S.grantii, S. compactum, M. lugardae, M. guentheri, and E. gossweileni,like that of E. peplus, induce the differentiation of MM96L cells to abipolar phenotype and that this differentiation is inhibited by thebisindolylmaleimide. This inhibition strongly suggests that the activecomponents of the saps induce cell differentiation by inhibition of PKCactivity. The results also show that at higher concentrations (10⁻⁴ andabove), the saps are effective in killilng MM96L cells.

EXAMPLE 25 Effect of Saps Derivedfrom Other Members of the EuphorbiaceaeFamily on JAM Cells

[0353] The saps of Example 24 were also examined for their cytotoxiceffect on the ovarian carcinoma cell line JAM. Ten-microlitre aliquotsof each dilution of sap, prepared according to Example 24 in thepresence or absence of the PKC inhibitor bisindolylmaleimide (10 μg/mL),or in the presence or absence of the PKC phorbol ester binding siteligand phorbol dibutyrate, were added to 5000 JAM cells per well of amicrotitre plate. After three days, the cells were fixed with ethanoland the number of cells compared with untreated controls stained withsulfurhodamine B.

[0354] The results presented in FIGS. 18A and 18B indicate that, likethe sap of Epeplus, the saps of S. grantii, S. compactum, M. Iugardae,M. guentheri, and E. gossweileni, at concentrations of 10⁻⁴ and above,are effective in killing JAM cells. These results also show thatcytotoxicity is inhibited by bisindolylmaleimide, suggesting that thiseffect is mediated by modulation of PKC.

[0355] Inspection of FIG. 18C reveals that the cytotoxic effects of sapsderived from M. guentheri and E. gossweileni were blocked in thepresence of phorbol dibutyrate, suggesting that the active components ofthese saps mediate their cytotoxicity by binding to the phorbol esterbinding site of PKC.

[0356] Those skilled in the art will appreciate that the inventiondescribed herein is susceptible to variations and modifications otherthan those specifically described. It is to be understood that theinvention includes all such variations and modifications. The inventionalso includes all of the steps, features, compositions and compoundsreferred to or indicated in this specification, individually orcollectively, and any and all combinations of any two or more of saidsteps or features.

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1. A method for the treatment or prophylaxis of a condition associatedwith the presence of a biological entity or part thereof or a toxin orvenom therefrom or a genetic event caused thereby in a subject, saidmethod comprising the administration to said subject of asymptom-ameliorating effective amount of a chemical agent obtainablefrom a plant of the Euphorbiaceae family or a derivative or chemicalanalogue thereof which chemical agent is a macrocyclic diterpeneselected from compounds of the ingenane, pepluane and jatrophanefamilies and which chemical agent or derivative or chemical analogue isrepresented by any one of the general forlulae (I)-(V):

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A-T are independently selected from hydrogen, R₁, R₂,R₃, F, Cl, Br, I, CN, OR₁, SR₁, NR₁R₂, N(═O)₂, NR₁OR₂, ONR₁R₂, SOR₁,SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂, SO₃NR₁R₂, P(R₁)₃, P(═O)(R₁)₃, Si(R₁)₃,B(R₁)₂, (C═X)R₃ or X(C═X)R₃ where X is selected from sulfur, oxygen andnitrogen; R₁ and R₂ are each independently selected from C₁-C₂₀ alkyl(branched and/or straight chained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀alkenyl(branched and/or straight chained), C₂-C₁₀ alkynyl (branched and/orstraight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₁, SR₁,NR₁R₂, N(═O)₂, NR₁OR₂, ONR₁R₂, SOR₁, SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂,SO₃NR₁R₂, P(R₁)₃, P(═O)(R₁)₃, Si(R₁)₃, B(R₁)₂]alkyl; R₃ is selected fromR₁, R₂, CN, COR₁, CO₂R₁, OR₁, SR₁, NR₁R₂, N(═O)₂, NR₁OR₂, ONR₁R₂, SOR₁,SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂, SO₃NR₁R₂, P(R₁)₃, P(═O)(R₁)₃, Si(R₁)₃,B(R₁)₂; A connected to B (or C), D (or E), R (or Q), P (or O) or S (orT) is a selection of C₁-C₈ disubstituted (fused) saturated orunsaturated carbocyclic or heterocyclic rings further substituted by R₃,(C═X)R₃ and X(C═X)R₃, including epoxides and thioepoxides; J connectedto I (or H), G (or F), K (or L), M (or N) or S (or T) is a selection ofC₁-C₈ disubstituted (fused) saturated and unsaturated carbocyclic orheterocyclic rings further substituted by R₃, (C═X)R₃ and X(C═X)R₃,including epoxides and thiocpoxides; D (or E) connected to B (or C) or G(or F); I (or H) connected to G (or F); P (or O) connected to R (or Q)or M (or N); K (or L) connected to N (or M) is a selection of C₁-C₈disubstituted (fused) saturated or unsaturated carbocyclic orheterocyclic rings substituted by R₃, (C═X)R₃ and X(C═X)R₃, includingepoxides and thioepoxides; B and C, D and E, R and Q, P and O, I and H,G and F, K and L, M and N or S and T are =X where X is selected fromsulfur, oxygen, nitrogen, NR₁R₂, and ═CR₁R₂

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen,sulfuir, phosphorus, silicon, boron, arsenic and selenium, wherein thering defined by said atoms is saturated or unsaturated, includingepoxides and thioepoxides; A′-T′ are independently selected fromhydrogen, R₄, R₅, R₆, F, Cl, Br, I, CN, COR₄, CO₂R₄, OR₄, SR₄, NR₄R₅,CONR₄R₅, N(═O)₂, NR₄OR₅, ONR₄R₅, SOR₄, SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅,SO₃Nk₄R₅, P(R₄)₃, P(═O)(R₄)₃, Si(R₄)₃, B(R₄)₂, (C═X)R₆ or X(C═X)R₆ whereX is selected from sulfur, oxygen and nitrogen; R₄ and R₅ are eachindependently selected from C₁-C₂₀ alkyl (branched and/or straightchained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl (branched and/or straightchained), C₂-C₁₀ alkynyl (branched and/or straight chained), C₁-C₁₀heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl,trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₄, SR₄, NR₄R₅, N(═O)₂, NR₄R₅,ONR₄R₅, SOR₄, SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅, SO3NR₄R₅, P(R₄)₃,P(═O)(R₄)₃, Si(R₄)₃, B(R₄)₂]alkyl; R₆ is selected from R₄, R₅, CN, COR₄,CO₂R₄, OR₄, SR₄, NR₄R₅, N(═O)₂, NR₄OR₅, ONRR₅, SOR₄, SO₂R₄, SO₃R₄,SONR₄R₅, SO₂NR₄R₅, SO₃NR₄R₅, P(R₄)₃, P(═O)(R₄)₃, Si(R₄)₃, B(R₄)₂; E′ andR′ or H′ and O′ is a C₂-C₈ saturated or unsaturated carbocyclic orheterocyclic ring system further substituted by R₆, including epoxidesand thioepoxides; O′ connected to M′ (or N′) or Q′ (or P′); R′ connectedto Q′ (or P′) or S′ (or T′); S′ (or T′) connected to A′ (or B′); A′ (orB′) connected to C′ (or D′); E′ connected to C′ (or D′) or F′ (or G′);H′ connected to I′; I′ connected to J′; J′ connected to K′; K′ connectedto L′; L′ connected to M′ (or N′) are C₁-C₈ disubstituted (fused)saturated or unsaturated carbocyclic or heterocyclic ring systemsfurther substituted by R₆, (C═X)R₆ and X(C═X)R₆, including epoxides andthioepoxides; A′, B′ and C′, D′ and F′, G′ and M′, N′ and P′, Q′ and S′,T′ are =X where X is selected from sulfur, oxygen, nitrogen, NR₄R₅,(C═X)R₆, X(C═X)R₆, and ═CR₇R₈; R₇ and R₈ are each independently selectedfrom R₆, (C═X)R₆ and X(C═X)R₆

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A¹-T¹ are independently selected from hydrogen, R₉,R₁₀, R₁₁, F, Cl, Br, I, CN, OR₉, SR₉, NR₉R₁₀, N(═O)₂, NR₉OR₁₀, ONR₉R₁₀,SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀, SO₂NR₉R₁₀, SO₃NR₉R₁₀, P(R₉)₃, P(═O)(R₉)₃,Si(R₉)₃, B(R₉)₂, (C═X)R₁₁ or X(C═X)R₁₁ where X is selected from sulfur,oxygen and nitrogen; R₉ and R₁₀ are each independently selected fromC₁-C₂₀ alkyl (branched and straight chained), C₁-C₂₀ arylalkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀alkenyl (branched and straight chained), C₂-C₁₀ alkynyl (branched andstraight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₉, SR₉,NR₉R₁₀, N(═O)₂, NR₉OR₁₀, ONR₉R₁₀, SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀,SO₂NR₉R₁₀, SO₃NR₉R₁₀, P(R₉)₃, P(═O)(R₉)₃, Si(R₉)₃, B(R₉)₂]alkyl; R₁₁ isselected from R₉, R₁₀, CN, COR₉, CO₂R₉, OR₉, SR₉, NR₉R₁₀, N(═O)₂,NR₉OR₁₀, ONR₉R₁₀, SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀, SO₂NR₉R₁₀, SO₃NR₉R₁₀,P(R₉)₃, P(═O)(R₉)₃, Si(R₉)₃, B(R₉)₂; B¹ and R¹, E¹ and Ö¹ and Ë¹ and M¹are selected from a C₂-C₈ saturated or unsaturated carbocyclic orheterocyclic ring system further substituted by R₁₁, including epoxidesand thioepoxides; A¹ (or Ä¹) connected to Á¹ (or Ã¹) or T¹ (or S¹); B¹connected to Á¹ (or Ã¹) or C¹ (or D¹). E¹ connected to Ë¹ or C¹ (or D¹);Ë¹ connected to É¹ (or F¹); G¹ (or H¹) connected to É¹ (or F¹) or I¹ (orJ¹); K¹ (or L¹) connected to I¹ (or J¹) or M¹; M¹ connected to O¹ (orN¹); Ö¹ connected O¹ (or N¹) or P¹ (or Q¹); R¹ connected P¹ (or Q¹) orS¹ (or T¹) are C₁-C₈ disubstituted (fused) saturated or unsaturatedcarbocyclic or heterocyclic ring systems further substituted by R₁₁,(C═X)R₁₁ and X(C═X)R₁₁, including epoxides and thioepoxides; A¹, Ä andÁ, Ã and C¹, D¹ and F¹, É and G¹, H¹ and I¹, J¹ and K¹, L¹ and N¹, O¹and P¹, Q¹ and S¹, T¹ are =X where X is selected from sulfur, oxygen,nitrogen, NR₉R₁₀, including (C═X)R₁₁ and X(C═X)R₁₁ and ═CR₁₂R₁₃; R₁₂ andR₁₃ are independently selected from R₁₁, (C═X)R₁₁ and X(C═X)R₁₁

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A²-X² are independently selected from hydrogen, R₁₄,R₁₅, R₁₆, F, Cl, Br, I, CN, OR₁₄, SR₁₄, NR₁₄R₁₅, N(═O)₂, NR₁₄OR₁₅,ONR₁₄R₁₅, SOR₁₄, SO₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅, SO₂NR₁₄R₁₅, SO₃NR₁₄R₁₅,P(R₁₄)₃, P(═O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄), (C═Y)R₁₆ or Y(C═Y)R₁₆ where Y isselected from sulfur, oxygen and nitrogen; R₁₄ and R₁₅ are eachindependently selected from C₁-C₂₀ alkyl (branched and/or straightchained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl (branched and/or straightchained), C₂-C₁₀ alkynyl (branched and/or straight chained), C₁-C₁₀heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl,trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₁₄, SR₁₄, NR₁₄R₁₀, N(═O)₂,NR₁₄OR₁₅, ONR₁₄R₁₅, SOR₁₄, SO₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅, SO₂NR₁₄R₁₅,SO₃NR₁₄R₁₅, P(R₁₄)₃, P(═O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄)₂]alkyl; R₁₆ isselected from R₁₄, R₁₅, CN, COR₁₄, CO₂R₁₅, OR₁₄, SR₁₄, NR₁₄R₁₅, N(═O)₂,NR₁₄OR₁₅, ONR₁₄R₁₅, SOR₁₄, SO₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅, SO₂NR₁₄R₁₅,SO₃NR₁₄R₁₅, P(R₁₄)₃, P(═O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄)₂; E² and V², H² andS², and I² and P² are C₂-C₈ saturated or unsaturated carbocyclic orheterocyclic ring system further substituted by R₁₆, including epoxidesand thioepoxides; A² (or B²) connected to C² (or D²) or W² (or X²); E²connected to C² (or D²) or F² (or G²); H² connected to F² (or G²) or I²;I² connected to J² (or K²); L² (or M²) connected to J² (or K²) or N² (orO²); R² (or Q²) connected to P² or S²; V² connected to U² (or T²) or W²(or X²) are C₁-C₈ disubstituted (fused) saturated or unsaturatedcarbocyclic or heterocyclic ring systems further substituted by R₁₆,(C═Y)R₁₆ and Y(C═Y)R₁₆, including epoxides and thioepoxides; A², B²; C²,D²; F², G²; J², K²; L², M²; N², O²; Q², R²; U², T² and X², W² are =Ywhere Y is selected from sulfur, oxygen, nitrogen, NR₁₄R₁₅ and ═CR₁₇R₁₈;R₁₇ and R₁₈ are independently selected from R₁₆, (C═Y)R₁₆ and Y(C═Y)R₁₆

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A³-Z³ are independently selected from hydrogen, R₁₉,R₂₀, R₂₁, F, Cl, Br, I, CN, OR₁₉, SR₁₉, NR₁₉R₂₀, N(═O)₂, NR₁₉OR₂₀,ONR₁₉R₂₀, SOR₁₉, SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀,P(R₁₉)₃, P(O)(R₁₉)₃, Si(R₁₉)₃, B(R₁₉)₂, (C═Ø)R₂₁ or Ø(C═Ø)R₂₁ where Ø issulfur, oxygen and nitrogen; R₁₉ and R₂₀ are each independently selectedfrom C₁-C₂₀ alkyl (branched and/or straight chained), C₁-C₂₀ arylalkyl,C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle,C₂-C₁₀ alkenyl (branched and/or straight chained), C₂-C₁₀ alkynyl(branched and/or straight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀alkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy,C₁-C₁₀ [CN, OR₁₉, SR₁₉, NR₁₉R₂₀, N(═O)₂, NR₁₉OR₂₀, ONR₁₉R₂₀, SOR₁₉,SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀, P(R₁₉)₃, P(═O)(R₁₉)₃,Si(R₁₉)₃, B(R₁₉)₂]alkyl; R₂₁ is selected from R₁₉, R₂₀, CN, COR₁₉,CO₂R₁₉, OR₁₉, SR₁₉, NR₁₉R₂₀, N(═O)₂, NR₁₉OR₂₀, ONR₁₉R₂₀, SOR₁₉, SO₂R₁₉,SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀, P(R₁₉)₃, P(═O)(R₁₉)₃,Si(R₁₉)₃, B(R₁₉)₂; D³ connected to X³ is a C₂-C₈ saturated orunsaturated carbocyclic or heterocyclic ring system further substitutedby R₂₁, including epoxides and thioepoxides; A³ (or Ä³) connected to B³(or C³) or Z³ (or Y³); D³ connected to B³ (or C³) or E³ (or F³); G³ (orH³) connected to E³ (or F³) or I³ (or J³); L³ (or K³) connected to I³(or J³) or M³ (or N³); O³ (or Ö³) connected to N³ (or M³) or P³ (or Q³).S³ (or R³) connected to Q³ (or P³) or U³ (or T³). W³ (or V³) connectedto U³ (or T³) or X³; X³ connected to Y³ (or Z³) are C₁-C₈ disubstituted(fused) saturated or unsaturated carbocyclic or heterocyclic ringsystems further substituted by R₂₁, (C═Ø)R₂₁ and Ø (C=Ø)R₂₁, includingepoxides and thioepoxides; A³, Ä³, B³, C³, E³, F³, G³, H³; I³, J³; K³;L³, M³, N³; O³, Ö³; Q³, P³, S³, R³, U³, T³, W³, V³, and Z³, Y³ are =Øwhere Ø is selected from sulfur, oxygen, nitrogen, NR₁₉R₂₀, and═CR₂₂R₂₃; and R₂₂ and R₂₃ are selected from R₂₁, (C=Ø)R₂₁ and Ø(C=Ø)R₂₁;and which chemical agent or derivative or chemical analogue thereof iscapable of modulating PKC activity, PKC-dependent gene expression or PKCenzyme turnover and wherein said chemical agent or its derivatives orchemical analogues is administered for a time and under conditionssufficient to ameliorate one or more symptoms associated with saidinflammatory condition.
 2. A method according to claim 1 wherein thechemical agent is represented by the general formula (VI):

wherein: R₂₄, R₂₅ and R₂₆ are independently selected from hydrogen, R₂₇,R₂₈, F, Cl, Br, I, CN, OR₂₇, SR₂₇, NR₂₇R₂₈, N(═O)₂, NR₂₇OR₂₈, ONR₂₇R₂₈,SOR₂₇, SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃,P(═O)(R₂₇)₃, Si(R₂₇)₃, B(R₂₇)₂, (C═X)R₂₉ or X(C═X)R₂₉ where X isselected from sulfur, oxygen and nitrogen; R₂₇ and R₂₈ are eachindependently selected from C₁-C₂₀ alkyl (branched and/or straightchained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl (branched and/or straightchained), C₂-C₁₀ alkynyl (branched and/or straight chained), C₁-C₁₀heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl,trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₂₇, SR₂₇, NR₂₇R₂₉, N(═O)₂,NR₂₇OR₂₈, ONR₂₇R₂₈, SOR₂₇, SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈,SO₃NR₂₇R₂₈, P(R₂₇)₃, P(═O)(R₂₇)₃, Si(R₂₇)₃, B(R₂₇)₂]alkyl; R₂₉ isselected from R₂₇, R₂₈, CN, COR₂₇, CO₂R₂₇, OR₂₇, SR₂₇, NR₂₇R₂₈, N(═O)₂,NR₂₇OR₂₈, ONR₂₇R₂₈, SOR₂₇, SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈,SO₃NR₂₇R₂₈, P(R₂₇)₃, P(═O)(R₂₇)₃, Si(R₂₇)₃, B(R₂₇)₂.
 3. A methodaccording to claim 2 wherein R₂₄ is H.
 4. A method according to claim 2wherein R₂₄ is OAcetyl.
 5. A method according to claim 2 wherein R₂₄ isOH.
 6. A method according to claim 2 wherein R₂₅ and R₂₆ are OH.
 7. Amethod according to claim 1 wherein the plant is of the genus selectedfrom Acalypha, Acidoton, Actinostemon, Adelia, Adenocline, Adenocrepis,Adenophaedra, Adisca, Agrostistachys, Alchornea, Alchorneopsis,Alcinaeanthus, Alcoceria, Aleurites, Amanoa, Andrachne, Angostyles,Anisophyllum, Antidesma, Aphora, Aporosa, Aporosella, Argythamnia,Astrococcus, Astrogyne, Baccanrea, Baliospermum, Bernardia, Beyeriopsis,Bischofia, Blachia, Blumeodondron, Bonania, Bradleia, Breynia,Breyniopsis, Briedelia, Buraeavia, Caperonia, Caryodendron, Celianella,Cephalocroton, Chaenotheca, Chaetocarpus, Chamaesyce, Cheilosa,Chiropetalum, Choriophyllum, Cicca, Chaoxylon, Cleidon, Cleistanthus,Cluytia, Cnesmone, Cnidoscolus, Coccoceras, Codiaeum, Coelodiscus,Conami, Conceveiba, Conceveibastrum, Conceveibum, Corythea, Croizatia,Croton, Crotonopsis, Crozophora, Cubanthus, Cunuria, Dactylostemon,Dalechampia, Dendrocousinsia, Diaspersus, Didymocistus, Dimorphocalyx,Discocarpus, Ditaxis, Dodecastingma, Drypetes, Dysopsis,Elateriospermum, Endadenium, Endospermum, Erismanthus, Erythrocarpus,Erythrochilus, Eumecanthus, Euphorbia, Euphorbiodendron, Excoecaria,Flueggea, Calearia, Garcia, Gavarretia, Gelonium, Giara, Givotia,Glochidion, Clochidionopsis, Glycydendron, Gymnanthes, Gymnosparia,Haematospermum, Hendecandra, Hevea, Hieronima, Hieronyma,Hippocrepandra, Homalanthus, Hymenocardia, Janipha, Jatropha,Julocroton, Lasiocroton, Leiocarpus, Leonardia, Lepidanthus,Leucocroton, Mabea, Macaranga, Mallotus, Manihot, Mappa, Maprounea,Melanthesa, Mercurialis, Mettenia, Micrandra, Microdesmis, Microelus,Microstachy, Maocroton, Monadenium, Mozinna, Neoscortechinia,Omalanthus, Omphalea, Ophellantha, Orbicularia, Ostodes, Oxydectes,Palenga, Pantadenia, Paradrypeptes, Pausandra, Pedilanthus, Pera,Peridium, Petalostigma, Phyllanthus, Picrodendro, Pierardia,Pilinophytum, Pimeleodendron, Piranhea, Platygyna, Plukenetia,Podocalyx, Poinsettia, Poraresia, Prosartema, Pseudanthus, Pycnocoma,Quadrasia, Reverchonia, Richeria, Richeriella, Ricinella, Ricinocarpus,Rottlera, Sagotia, Sanwithia, Sapium, Savia, Sclerocroton, Sebastiana,Securinega, Senefeldera, Senefilderopsis, Serophyton, Siphonia,Spathiostemon, Spixia, Stillingia, Strophioblachia, Synadenium,Tetracoccus, Tetraplandra, Tetrorchidium, Thyrsanthera, Tithymalus,Trageia, Trewia, Trigonostemon, Tyria and Xylophylla.
 8. A methodaccording to claim 7 wherein the plant is of the genus Euphorbia.
 9. Amethod according to claim 8 wherein the species of Euphorbia is selectedfrom Euphorbia aaron-rossii, Euphorbia abbreviata, Euphorbia acuta,Euphorbia alatocaulis, Euphorbia albicaulis, Euphorbia algomarginata,Euphorbia aliceae, Euphorbia alta, Euphorbia anacampseros, Euphorbiaandromedae, Euphorbia angusta, Euphorbia anthonyi, Euphorbiaantiguensis, Euphorbia apocynifolia, Euphorbia arabica, Euphorbiaariensis, Euphorbia arizonica, Euphorbia arkansana, Euphorbia arteagae,Euphorbia arundelana, Euphorbia astroites, Euphorbia atrococca,Euphorbia baselicis, Euphorbia batabanensis, Euphorbia bergeri,Euphorbia bermudiana, Euphorbia bicolor, Euphorbia biformis, Euphorbiabifurcata, Euphorbia bilobata, Euphorbia biramensis, Euphorbiabiuncialis, Euphorbia blepharostipula, Euphorbia blodgetti, Euphorbiaboerhaavioides, Euphorbia boliviana, Euphorbia bracei, Euphorbiabrachiata, Euphorbia brachycera, Euphorbia brandegee, Euphorbiabrittonii, Euphorbia caesia, Euphorbia calcicola, Euphorbia campestris,Euphorbia candelabrum, Euphorbia capitellata, Euphorbia carmenensis,Euphorbia carunculata, Euphorbia cayensis, Euphorbia celastroides,Euphorbia chalicophila, Euphorbia chamaerrhodos, Euphorbia chamaesula,Euphorbia chiapensis, Euphorbia chiogenoides, Euphorbia cinerascens,Euphorbia clarionensis, Euphorbia colimae, Euphorbia colorata, Euphorbiacommutata, Euphorbia consoquitlae, Euphorbia convolvuloides, Euphorbiacorallifera, Euphorbia creberrima, Euphorbia crenulata, Euphorbiacubensis, Euphorbia cuspidata, Euphorbia cymbiformis, Euphorbiadarlingtonii, Euphorbia defoliata, Euphorbia degeneri, Euphorbiadeltoidea, Euphorbia dentata, Euphorbia depressa Euphorbia dictyosperma,Euphorbia dictyosperma, Euphorbia dioeca, Euphorbia discoidalis,Euphorbia dorsiventralis, Euphorbia drumondii, Euphorbia duclouxii,Euphorbia dussii, Euphorbia eanophylla, Euphorbia eggersii, Euphorbiaeglandulosa, Euphorbia elata, Euphorbia enalla, Euphorbia eriogonoides,Euphorbia eriophylla, Euphorbia esculaeformis, Euphorbia espirituensis,Euphorbia esula, Euphorbia excisa, Euphorbia exclusa, Euphorbiaexstipitata, Euphorbia exstipulata, Euphorbia fendleri, Euphorbiafilicaulis, Euphorbia filiformis, Euphorbia florida, Euphorbiafruticulosa, Euphorbia garber, Euphorbia gaumerii, Euphorbia gerardiana,Euphorbia geyeri, Euphorbia glyptosperma, Euphorbia gorgonis, Euphorbiagracilior, Euphorbia gracillima, Euphorbia gradyi, Euphorbia graminea,Euphorbia graminiea Euphorbia grisea, Euphorbia guadalajarana, Euphorbiaguanarensis, Euphorbia gymnadenia, Euphorbia haematantha, Euphorbiahedyotoides, Euphorbia heldrichii, Euphorbia helenae, Euphorbia helleri,Euphorbia helwigii, Euphorbia henricksonii, Euphorbia heterophylla,Euphorbia hexagona, Euphorbia hexagonoides, Euphorbia hinkleyorum,Euphorbia hintonii, Euphorbia hirtula, Euphorbia hirta, Euphorbiahooveri, Euphorbia humistrata, Euphorbia hypericifolia, Euphorbiainundata, Euphorbia involuta, Euphorbia jaliscensis, Euphorbia jejuna,Euphorbia johnston, Euphorbia juttae, Euphorbia knuthii, Euphorbialasiocarpa, Euphorbia lata, Euphorbia latazi, Euphorbia latericolor,Euphorbia laxiflora Euphorbia lecheoides, Euphorbia ledienii, Euphorbialeucophylla, Euphorbia lineata, Euphorbia linguiformis, Euphorbialongecornuta, Euphorbia longepetiolata, Euphorbia longeramosa, Euphorbialonginsulicola, Euphorbia longipila, Euphorbia lupulina, Euphorbialurida, Euphorbia lycioides, Euphorbia macropodoides, macvaughiana,Euphorbia manca, Euphorbia mandoniana, Euphorbia mangleti, Euphorbiamango, Euphorbia marylandica, Euphorbia mayana, Euphorbia melanadenia,Euphorbia melanocarpa, Euphorbia meridensis, Euphorbia mertonii,Euphorbia mexiae, Euphorbia microcephala, Euphorbia microclada,Euphorbia micromera, Euphorbia misella, Euphorbia missurica, Euphorbiamontana, Euphorbia montereyana, Euphorbia multicaulis, Euphorbiamultiformis, Euphorbia multinodis, Euphorbia multiseta, Euphorbiamuscicola, Euphorbia neomexicana, Euphorbia nephradenia, Euphorbianiqueroana, Euphorbia oaxacana, Euphorbia occidentalis, Euphorbiaodontodenia, Euphorbia olivacea, Euphorbia olowaluana, Euphorbiaopthalmica, Euphorbia ovata, Euphorbia pachypoda, Euphorbia pachyrhiza,Euphorbia padifolia, Euphorbia palmeri, Euphorbia paludicola, Euphorbiaparciflora, Euphorbia parishii, Euphorbia parryi, Euphorbia paxiana,Euphorbia pediculifera, Euphorbia peplidion, Euphorbia peploides,Euphorbia peplus, Euphorbia pergamena, Euphorbia perlignea, Euphorbiapetaloidea, Euphorbia petaloidea, Euphorbia petrina, Euphorbiapicachensis, Euphorbia pilosula, Euphorbia pilulifera, Euphorbiapinariona, Euphorbia pinetorum, Euphorbia pionosperma, Euphorbiaplatysperma, Euphorbia plicata, Euphorbia poeppigii, Euphorbiapoliosperma, Euphorbia polycarpa, Euphorbia polycnemoides, Euphorbiapolyphylla, Euphorbia portoricensis, Euphorbia portulacoides Euphorbiaportulana, Euphorbia preslii, Euphorbia prostrata, Euphorbia pteroneura,Euphorbia pycnanthema, Euphorbia ramosa, Euphorbia rapulum, Euphorbiaremyi, Euphorbia retroscabra, Euphorbia revoluta, Euphorbia rivularis,Euphorbia robusta, Euphorbia romosa, Euphorbia rubida, Eiphorbiarubrosperma, Euphorbia rupicola, Euphorbia sanmartensis, Euphorbiasaxatilis M. Bieb, Euphorbia schizoloba, Euphorbia sclerocyathium,Euphorbia scopulorum, Euphorbia senilis, Euphorbia serpyllifolia,Euphorbia serrula, Euphorbia setiloba Engelm, Euphorbia sonorae,Euphorbia soobyi, Euphorbia sparsiflora, Euphorbia sphaerosperma,Euphorbia syphilitica, Euphorbia spruceana, Euphorbia subcoerulea,Euphorbia stellata, Euphorbia submammilaris, Euphorbia subpeltata,Euphorbia subpubens, Euphorbia subreniforme, Euphorbia subtrifoliata,Euphorbia succedanea, Euphorbia tamaulipasana, Euphorbia telephioides,Euphorbia tenuissima, Euphorbia tetrapora, Euphorbia tirucalli,Euphorbia tomentella, Euphorbia tomentosa, Euphorbia torralbasii,Euphorbia tovariensis, Euphorbia trachysperma, Euphorbia tricolor,Euphorbia troyana, Euphorbia tuerckheimii, Euphorbia turczaminowii,Euphorbia umbellulata, Euphorbia undulata, Euphorbia vermiformis,Euphorbia versicolor, Euphorbia villifera, Euphorbia violacea, Euphorbiawhitei, Euphorbia xanti Engelm, Euphorbia xylopoda Greenm., Euphorbiayayalesia Urb., Euphorbia yungasensis, Euphorbia zeravschanica andEuphorbia zinniiflora.
 10. A method according to claim 9 wherein thespecies of Euphorbia is Euphorbia peplus.
 11. A method according toclaim 1 wherein the biological entity is a prokaryotic microorganism.12. A method according to claim 11 wherein the prokaryotic microorganismis a species of Treponema sp., Borrelia sp., Neisseria sp., Legionellasp., Bordetella sp., Escherichia sp., Salmonella sp., Shigella sp.,Klebsiella sp., Yersinia sp., Vibrio sp., Hemophilus sp., Rickettsiasp., Chlamydia sp., Mycoplasma sp., Staphylococcus sp., Streptococcussp., Bacillus sp., Clostridium sp., Corynebacterium sp.,Proprionibacterium sp., Mycobacterium sp., Ureaplasma sp. and Listeriasp.
 13. A method according to claim 12 wherein the prokaryoticmicroorganism is selected from Treponema pallidum, Borrelia burgdorferi,Neisseria gonorrhea, Neisseria meningitidis, Legionella pneumophila,Bordetella pertussis, Escherichia coli, Salmonella typhi, Salmonellatyphimurium, Shigella dysenteriae, Klebsiella pneumoniae, Yersiniapestis, Vibrio cholerae, Hemophilus influenzae, Rickettsia rickettsii,Chlamydia trachomatis, Mycoplasma pneumoniae, Staphylococcus aureus,Streptococcus pneumoniae, Streptococcus pyogenes, Bacillus anthracis,Clostridium botulinum, Clostridium tetani, Clostridium perfringens,Corynebacterium diphtheriae, Proprionibacterium acnes, Mycobacteriumtuberculosis, Mycobacterium leprae, Ureaplasma parvum and Listeriamonocytogenes.
 14. A method according to claim 13 wherein theprokaryotic organism is a Salmonella typhi, Salmonella typhimurium,Streptococcus pneumoniae, Streptococcus pyogenes and Staphylococcusaureus.
 15. A method according to 1 wherein the biological entity is alower eukaryotic microorganism.
 16. A method according to claim 15wherein the lower eukaryotic organism is a yeast or fungus selected fromPneumocystis carinii, Candida albicans, Aspergillus, Histoplasmacapsulatum, Blastomyces dermatitidis, Cryptococcus neoformans,Trichophyton and Microsporum.
 17. A method according to claim 1 whereinthe biological entity is a complex eukaryotic organism.
 18. A methodaccording to claim 17 wherein the complex eukaryotic organism isselected from worms, insects, arachnids, nematodes, aemobe, Entamoebahistolytica, Giardia lamblia, Trichomonas vaginalis, Trypanosoma bruceigambiense, Trypanosoma cruzi, Balantidium coli, Toxoplasma gondii,Cryptosporidium or Leishmania.
 19. A method according to claim 1 whereinthe biological entity is a virus.
 20. A method according to claim 19wherein the virus is selected from adenoviruses, papovaviruses,herpesviruses: simplex, varicella-zoster, Epstein-Barr, CMV, poxviruses: smallpox, vaccinia, hepatitis B, rhinoviruses, hepatitis A,poliovirus, rubellavirus, hepatitis C, arboviruses, rabiesvirus,influenzaviruses A and B, measlesvirus, mumpsvirus, HIV, HTLV I and II.21. A method according to claim 20 wherein the virus is HIV, HTLV 1 orHTLV II.
 22. A method according to claim 21 wherein the virus is HIV.23. A method according to claim 20 wherein the virus is Epstein-Barrvirus.
 24. A method according to claim 1 wherein the chemical agent is ajatrophane or a derivative thereof or a pharmaceutically acceptable saltof these.
 25. A method according to claim 24 wherein said derivative isan ester derivative.
 26. A method according to claim 24 wherein saidderivative is an acetylated derivative.
 27. A method according to claim1 wherein said chemical agent is a pepluane or a derivative thereof or apharmaceutically acceptable salt of these.
 28. A method according toclaim 27 wherein said derivative is an ester derivative.
 29. A methodaccording to claim 27 wherein said derivative is an acetylatedderivative.
 30. A method according to claim 1 wherein said chemicalagent is a paraliane or a derivative thereof or a pharmaceuticallyacceptable salt of these.
 31. A method according to claim 30 whereinsaid derivative is an ester derivative.
 32. A method according to claim30 wherein said derivative is an acetylated derivative.
 33. A methodaccording to claim 1 wherein said compound is an angeloyl-substitutedingenane or a derivative thereof or a pharmaceutically acceptable saltof these.
 34. A method according to claim 33 wherein said derivative isan acetylated derivative.
 35. A method according to claim 33 whereinsaid jatrophane is of conformation
 2. 36. A method according to claim 24or 27 or 30 or 33 wherein the derivative comprises a substitution asrepresented in any one of general formulae (I)-(VI).
 37. A methodaccording to claim 1 wherein said compound is5,8,9,10,14-pentaacetoxy-3-benzoyloxy-15-hydroxypepluane (pepluane) or aderivative thereof or a pharmaceutically acceptable salt of these.
 38. Amethod according to claim 37 wherein said derivative is an esterderivative.
 39. A method according to claim 1 wherein said compound is2,3,5,7,15-pentaacetoxy-9-nicotinoyloxy-14-oxojatropha-6(17),11E-diene(jatrophane 1) or a derivative thereof or a pharmaceutically acceptablesalt of these.
 40. A method according to claim 39 wherein saidderivative is an ester derivative.
 41. A method according to claim 1wherein said compound is2,5,7,8,9,14-hexaacetoxy-3-benzoyloxy-15-hydroxy-jatropha-6(17),11E-diene(jatrophane 2) or a derivative thereof or a pharmaceutically acceptablesalt of these.
 42. A method according to claim 41 wherein saidderivative is an ester derivative.
 43. A method according to claim 1wherein said compound is2,5,14-triacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxy-9-nicotinoyloxyjatropha-6(17),11E-diene (jatrophane 3) or a derivative thereof or a pharmaceuticallyacceptable salt of these.
 44. A method according to claim 43 whereinsaid derivative is an ester derivative.
 45. A method according to claim1 wherein said compound is2,5,9,14-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxyjatropha-6(17),11E-diene) (jatrophane 4) or a derivative thereof or a pharmaceuticallyacceptable salt of these.
 46. A method according to claim 45 whereinsaid derivative is an ester derivative.
 47. A method according to claim1 wherein said compound is2,5,7,14-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-9-nicotinoyloxyjatropha-6(17),11E-diene (jatrophane 5) or a derivative thereof or a pharmaceuticallyacceptable salt of these.
 48. A method according to claim 47 whereinsaid derivative is an ester derivative.
 49. A method according to claim1 wherein said compound is2,5,7,9,14-pentaacetoxy-3-benzoyloxy-8,15-dihydroxyjatropha-6(17),11E-diene (jatrophane 6) or a derivative thereof or a pharmaceuticallyacceptable salt of these.
 50. A method according to claim 49 whereinsaid derivative is an ester derivative.
 51. A method according to claim1 wherein said compound is 20-O-acetyl-ingenol-3-angelate or aderivative thereof or a pharmaceutically acceptable salt of these.
 52. Amethod according to claim 51 wherein said derivative is an esterderivative.
 53. A method according to claim 1 or 24 or 27 or 30 or 33 or37 or 39 or 41 or 43 or 45 or 47 or 49 or 52 wherein said compound isprovided in the form of a composition comprising a pharmaceutically- orcosmetically-acceptable carrier.
 54. A method according to claim 53wherein said carrier is selected from β-alanine betaine hydrochlorideand t-4-hydroxy-N,N-dimethylproline.
 55. A method for the treatment orprophylaxis of an an innate viral infection, said method comprisingadministration to said subject of a virus-activating effective amount ofa macrocyclic diterpene obtainable from a Euphorbiaceae plant or itsbotanical or horticultural relative, said macrocyclic diterpene beingselected from an ingenane, pepluane or jatrophane, or a derivative orchemical analogue thereof, having the structure represented by any oneof the general formulae (I)-(V)

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A-T are independently selected from hydrogen, R₁, R₂,R₃, F, Cl, Br, I, CN, OR₁, SR₁, NR₁R₂, N(═O)₂, NR₁OR₂, ONR₁R₂, SOR₁,SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂, SO₃NR₁R₂, P(R₁)₃, P(═O)(R₁)₃, Si(R₁)₃,B(R₁)₂, (C═X)R₃ or X(C═X)R₃ where X is selected from sulfur, oxygen andnitrogen; R₁ and R₂ are each independently selected from C₁-C₂₀ alkyl(branched and/or straight chained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl,C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl(branched and/or straight chained), C₂-C₁₀ alkynyl (branched and/orstraight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₁, SR₁,NR₁R₂, N(═O)₂, NR₁OR₂, ONR₁R₂, SOR₁, SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂,SO₃NR₁R₂, P(R₁)₃, P(═O)(R₁)₃, Si(R₁)₃, B(R₁)₂]alkyl; R₃ is selected fromR₁, R₂, CN, COR₁, CO₂R₁, OR₁, SR₁, NR₁R₂, N(═O)₂, NR₁OR₂, ONR₁R₂, SOR₁,SO₂R₁, SO₃R₁, SONR₁R₂, SO₂NR₁R₂, SO₃NR₁R₂, P(R₁)₃, P(═O)(R₁)₃, Si(R₁)₃,B(R₁)₂; A connected to B (or C), D (or E), R (or Q), P (or O) or S (orT) is a selection of C₁-C₈ disubstituted (fused) saturated orunsaturated carbocyclic or heterocyclic rings further substituted by R₃,(C═X)R₃ and X(C═X)R₃, including epoxides and thioepoxides; J connectedto I (or H), G (or F), K (or L), M (or N) or S (or T) is a selection ofC₁-C₈ disubstituted (fused) saturated and unsaturated carbocyclic orheterocyclic rings further substituted by R₃, (C═X)R₃ and X(C═X)R₃,including epoxides and thioepoxides; D (or E) connected to B (or C) or G(or F); I (or H) connected to G (or F); P (or O) connected to R (or Q)or M (or N); K (or L) connected to N (or M) is a selection of C₁-C₈disubstituted (fused) saturated or unsaturated carbocyclic orheterocyclic rings substituted by R₃, (C═X)R₃ and X(C═X)R₃, includingepoxides and thioepoxides; B and C, D and E, R and Q, P and O, I and H,G and F, K and L, M and N or S and T are =X where X is selected fromsulfur, oxygen, nitrogen, NR₁R₂, and ═CR₁R₂

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A′-T′ are independently selected from hydrogen, R₄,R₅, R₆, F, Cl, Br, I, CN, COR₄, CO₂R₄, OR₄, SR₄, NR₄R₅, CONR₄R₅, N(═O)₂,NR₄OR₅, ONR₄R₅, SOR₄, SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅, SO₃NR₄R₅, P(R₄)₃,P(═O)(R₄)₃, Si(R₄)₃, B(R₄)₂, (C═X)R₆ or X(C═X)R₆ where X is selectedfrom sulfur, oxygen and nitrogen; R₄ and R₅ are each independentlyselected from C₁-C₂₀ alkyl (branched and/or straight chained), C₁-C₂₀arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄heterocycle, C₂-C₁₀ alkenyl (branched and/or straight chained), C₂-C₁₀alkynyl (branched and/or straight chained), C₁-C₁₀ heteroarylalkyl,C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl, trihaloalkyl,haloalkoxy, C₁-C₁₀ [CN, OR₄, SR₄, NR₄R₅, N(═O)₂, NR₄OR₅, ONR₄R₅, SOR₄,SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅, SO₃NR₄R₅, P(R₄)₃, P(═O)(R₄)₃, Si(R₄)₃,B(R₄)₂]alkyl; R₆ is selected from R₄, R₅, CN, COR₄, CO₂R₄, OR₄, SR₄,NR₄R₅, N(═O)₂, NR₄OR₅, ONR₄R₅, SOR₄, SO₂R₄, SO₃R₄, SONR₄R₅, SO₂NR₄R₅,SO₃NR₄R₅, P(R₄)₃, P(═O)(R₄)₃, Si(R₄)₃, B(R₄)₂; E′ and R′ or H′ and O′ isa C₂-C₈ saturated or unsaturated carbocyclic or heterocyclic ring systemfurther substituted by R₆, including epoxides and thioepoxides; O′connected to M′ (or N′) or Q′ (or P′); R′ connected to Q′ (or P′) or S′(or T′); S′ (or T′) connected to A′ (or B′); A′ (or B′) connected to C′(or D′); E′ connected to C′ (or D′) or F′ (or G′); H′ connected to I′;I′ connected to J′; J′ connected to K′; K′ connected to L′; L′ connectedto M′ (or N′) are C₁-C₈ disubstituted (fused) saturated or unsaturatedcarbocyclic or heterocyclic ring systems further substituted by R₆,(C═X)R₆ and X(C═X)R₆, including epoxides and thioepoxides; A′, B′ andC′, D′ and F′, G′ and M′, N′ and P′, and S′, T′ are =X where X isselected from sulfur, oxygen, nitrogen, NR₄R₅, (C═X)R₆, X(C═X)R₆, and═CR₇R₈; R₇ and R₈ are each independently selected from R₆, (C═X)R₆ andX(C═X)R₆

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A¹-T¹ are independently selected from hydrogen, R₉,R₁₀, R₁₁, F, Cl, Br, I, CN, OR₉, SR₉, NR₉R₁₀, N(═O)₂, NR₉OR₁₀, ONR₉R₁₀,SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀, SO₂NR₉R₁₀, SO₃NR₉R₁₀, P(R₉)₃, P(═O)(R₉)₃,Si(R₉)₃, B(R₉)₂, (C═X)R₁₁ or X(C═X)R₁₁ where X is selected from sulfur,oxygen and nitrogen; R₉ and R₁₀ are each independently selected fromC₁-C₂₀ alkyl (branched and straight chained), C₁-C₂₀ arylalkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄ heterocycle,C₂-C₁₀alkenyl (branched and straight chained), C₂-C₁₀ alkynyl (branchedand straight chained), C₁-C₁₀ heteroarylalkyl, C₁-C₁₀ alkoxyalkyl,C₁-C₁₀ haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN,OR₉, SR₉, NR₉R₁₀, N(═O)₂, NR₉OR₁₀, ONR₉R₁₀, SOR₉, SO₂R₉, SO₃R₉,SONR₉R₁₀, SO₂NR₉R₁₀, SO₃NR₉R₁₀, P(R₉)₃, P(═O)(R₉)₃, Si(R₉)₃,B(R₉)₂]alkyl; R₁₁ is selected from R₉, R₁₀, CN, COR₉, CO₂R₉, OR₉, SR₉,NR₉R₁₀, N(═O)₂, NR₉OR₁₀, ONR₉R₁₀, SOR₉, SO₂R₉, SO₃R₉, SONR₉R₁₀,SO₂NR₉R₁₀, SO₃NR₉R₁₀, P(R₉)₃, P(═O)(R₉)₃, Si(R₉)₃, B(R₉)₂; B¹ and R¹, E¹and Ö¹ and Ë¹ and M¹ are selected from a C₂-C₈ saturated or unsaturatedcarbocyclic or heterocyclic ring system further substituted by R₁₁including epoxides and thioepoxides; A¹ (or Ä¹) connected to Á¹ (or Ã¹)or T¹ (or S¹); B¹ connected to Á¹ (or Ã¹) or C¹ (or D¹). E¹ connected toË¹ or C¹ (or D¹); Ë¹ connected to É¹ (or F¹); G¹ (or H¹) connected to É¹(or F¹) or I¹ (or J¹); K¹ (or L¹) connected to I¹ (or J¹) or M¹; M¹connected to O¹ (or N¹); Ö¹ connected O¹ (or N¹) or P¹ (or Q¹); R¹connected P¹ (or Q¹) or S¹ (or T¹) are C₁-C₈ disubstituted (fused)saturated or unsaturated carbocyclic or heterocyclic ring systemsfurther substituted by R₁₁ (C═X)R₁₁ and X(C═X)R₁₁, including epoxidesand thioepoxides; A¹, Ä and Á, Ã and C¹, D¹ and F¹, É and G¹, H¹ and I¹,J¹ and K¹, L¹ and N¹, O¹ and P¹, Q¹ and S¹, T¹ are =X where X isselected from sulfur, oxygen, nitrogen, NR₉R₁₀, including (C═X)R₁₁ andX(C═X)R₁₁, and ═CR₁₂R₁₃; R₁₂ and R₁₃ are independently selected fromR₁₁, (C═X)R₁₁ and X(C═X)R₁₁

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A²-X² are independently selected from hydrogen, R₁₄,R₁₅, R₁₆, F, Cl, Br, I, CN, OR₁₄, SR₁₄, NR₁₄R₁₅, N(═O)₂, NR₁₄OR₁₅,ONR₁₄R₁₅, SOR₁₄, SO₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅, SO₂NR₁₄R₁₅, SO₃NR₁₄R₁₅,P(R₁₄)₃, P(═O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄), (C═Y)R₁₆ or Y(C═Y)R₁₆ where Y isselected from sulfur, oxygen and nitrogen; R₁₄ and R₁₅ are eachindependently selected from C₁-C₂₀ alkyl (branched and/or straightchained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl (branched and/or straightchained), C₂-C₁₀ alkynyl (branched and/or straight chained), C₁-C₁₀heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl,trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₁₄, SR₁₄, NR₁₄R₁₀, N(═O)₂,NR₁₄OR₁₅, ONR₁₄R₁₅, SOR₁₄, SO₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅, SO₂NR₁₄R₁₅,SO₃NR₁₄R₁₅, P(R₁₄)₃, P(═O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄)₂]alkyl; R₁₆ isselected from R₁₄, R₁₅, CN, COR₁₄, CO₂R₁₅, OR₁₄, SR₁₄, NR₁₄R₁₅, N(═O)₂,NR₁₄OR₁₅, ONR₁₄R₁₅, SOR₁₄, SO₂R₁₄, SO₃R₁₄, SONR₁₄R₁₅, SO₂NR₁₄R₁₅,SO₃NR₁₄R₁₅, P(R₁₄)₃, P(═O)(R₁₄)₃, Si(R₁₄)₃, B(R₁₄)₂; E² and V², H² andS², and I² and P² are C₂-C₈ saturated or unsaturated carbocyclic orheterocyclic ring system further substituted by R₁₆, including epoxidesand thioepoxides; A² (or B²) connected to C² (or D²) or W² (or X²); E²connected to C² (or D²) or F² (or G²); H² connected to F² (or G²) or I²;I² connected to J² (or K²); L² (or M²) connected to J² (or K²) or N² (orO²); R² (or Q²) connected to P² or S²; V² connected to U² (or T²) or W²(or X²) are C₁-C₈ disubstituted (fused) saturated or unsaturatedcarbocyclic or heterocyclic ring systems further substituted by R₁₆,(C═Y)R₁₆ and Y(C═Y)R₁₆, including epoxides and thioepoxides; A², B²; C²,D²; F², G²; J², K²; L² M²; N², O²; Q², R²; U², T² and X², W² are =Ywhere Y is selected from sulfur, oxygen, nitrogen, NR₁₄R₁₅ and ═CR₁₇R₁₈;R₁₇ and R₁₈ are independently selected from R₁₆, (C═Y)R₁₆ and Y(C═Y)R¹⁶

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur,phosphorus, silicon, boron, arsenic and selenium, wherein the ringdefined by said atoms is saturated or unsaturated, including epoxidesand thioepoxides; A³-Z³ are independently selected from hydrogen, R₁₉,R₂₀, R₂₁, F, Cl, Br, I, CN, OR₁₉, SR₁₉, NR₁₉R₂₀, N(═O)₂, NR₁₉OR₂₀,ONR₁₉R₂₀, SOR₁₉, SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀,P(R₁₉)₃, P(═O)(R₁₉)₃, Si(R₁₉)₃, B(R₁₉)₂, (C═Ø)R₂₁ or Ø(C═Ø)R₂₁ where Øis sulfur, oxygen and nitrogen; R₁₉ and R₂₀ are each independentlyselected from C₁-C₂₀ alkyl (branched and/or straight chained), C₁-C₂₀arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄ heteroaryl, C₁-C₁₄heterocycle, C₂-C₁₀ alkenyl (branched and/or straight chained), C₂-C₁₀alkynyl (branched and/or straight chained), C₁-C₁₀ heteroarylalkyl,C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl, trihaloalkyl,haloalkoxy, C₁-C₁₀[CN, OR₁₉, SR₁₉, NR₁₉R₂₀, N(O)₂, NR₁₉OR₂₀, ONR₁₉R₂₀,SOR₁₉, SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀, P(R₁₉)₃,P(═O)(R₁₉)₃, Si(R₁₉)₃, B(R₁₉)₂]alkyl; R₂₁ is selected from R₁₉, R₂₀, CN,COR₁₉, CO₂R₁₉, OR₁₉, SR₁₉, NR₁₉R₂₀, N(═O)₂, NR₁₉OR₂₀, ONR₁₉R₂₀, SOR₁₉,SO₂R₁₉, SO₃R₁₉, SONR₁₉R₂₀, SO₂NR₁₉R₂₀, SO₃NR₁₉R₂₀, P(R₁₉)₃, P(═O)(R₁₉)₃,Si(R₁₉)₃, B(R₁₉)₂; D³ connected to X³ is a C₂-C₈ saturated orunsaturated carbocyclic or heterocyclic ring system further substitutedby R₂₁, including epoxides and thioepoxides; A³ (or Ä³) connected to B³(or C³) or Z³ (or Y³); D³ connected to B³ (or C³) or E³ (or F³); G³ (orH³) connected to E³ (or F³) or I³ (or J³); L³ (or K³) connected to I³(or J³) or M³ (or N³); O³ (or Ö³) connected to N³ (or M³) or P³ (or Q³).S³ (or R³) connected to Q³ (or P³) or U³ (or T³). W³ (or V³) connectedto U³ (or T³) or X³; X³ connected to Y³ (or Z³) are C₁-C₈ disubstituted(fused) saturated or unsaturated carbocyclic or heterocyclic ringsystems further substituted by R₂₁, (C=Ø)R₂₁ and Ø (C=Ø)R₂₁, includingepoxides and thioepoxides; A³, Ä³; B³, C³; E³, F³; G³, H³; I³ J³; K³,L³; M³, N³; O³, Ö³; Q³, P³, S³, R³, U³, T³, W³, V³, and Z³, Y³ are =Øwhere Ø is selected from sulfur, oxygen, nitrogen, NR₁₉R₂₀, and═CR₂₂R₂₃; and R₂₂ and R₂₃ are selected from R₂₁, (C=Ø)R₂₁ and Ø(C=Ø)R₂₁;and which chemical agent or derivative or chemical analogue thereof iscapable of modulating PKC activity, PKC-dependent gene expression or PKCenzyme turnover and wherein said chemical agent or its derivatives orchemical analogues is administered for a time and under conditionssufficient to ameliorate one or more symptoms associated with saidvirus.
 56. A method according to claim 55 wherein the chemical agent isrepresented by the general formula (VI):

wherein: R₂₄, R₂₅ and R₂₆ are independently selected from hydrogen, R₂₇,R₂₈, F, Cl, Br, I, CN, OR₂₇, SR₂₇, NR₂₇R₂₈, N(═O)₂, NR₂₇OR₂₈, ONR₂₇R₂₈,SOR₂₇, SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈, SO₃NR₂₇R₂₈, P(R₂₇)₃,P(═O)(R₂₇)₃, Si(R₂₇)₃, B(R₂₇)₂, (C═X)R₂₉ or X(C═X)R₂₉ where X isselected from sulfur, oxygen and nitrogen; R₂₇ and R₂₈ are eachindependently selected from C₁-C₂₀ alkyl (branched and/or straightchained), C₁-C₂₀ arylalkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₁-C₁₄heteroaryl, C₁-C₁₄ heterocycle, C₂-C₁₀ alkenyl (branched and/or straightchained), C₂-C₁₀ alkynyl (branched and/or straight chained), C₁-C₁₀heteroarylalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ haloalkyl, dihaloalkyl,trihaloalkyl, haloalkoxy, C₁-C₁₀ [CN, OR₂₇, SR₂₇, NR₂₇R₂₈, N(═O)₂,NR₂₇OR₂₈, ONR₂₇R₂₈, SOR₂₇, SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈,SO₃NR₂₇R₂₈, P(R₂₇)₃, P(═O)(R₂₇)₃, Si(R₂₇)₃, B(R₂₇)₂]alkyl; R₂₉ isselected from R₂₇, R₂₈, CN, COR₂₇, CO₂R₂₇, OR₂₇, SR₂₇, NR₂₇R₂₉, N(═O)₂,NR₂₇OR₂₈, ONR₂₇R₂₈, SOR₂₇, SO₂R₂₇, SO₃R₂₇, SONR₂₇R₂₈, SO₂NR₂₇R₂₈,SO₃NR₂₇R₂₈, P(R₂₇)₃, P(═O)(R₂₇)₃, Si(R₂₇)₃, B(R₂₇)₂.
 57. A methodaccording to claim 56 wherein R₂₄ is H.
 58. A method according to claim56 wherein R₂₄ is OAcetyl.
 59. A method according to claim 56 whereinR₂₄ is OH.
 60. A method according to claim 56 wherein R₂₅ and R₂₆ areOH.
 61. A method according to claim 55 wherein the plant is of the genusselected from Acalypha, Acidoton, Actinostemon, Adelia, Adenocline,Adenocrepis, Adenophaedra, Adisca, Agrostistachys, Alchornea,Alchorneopsis, Alcinaeanthus, Alcoceria, Aleurites, Amnanoa, Andrachne,Angostyles, Anisophyllum, Antidesma, Aphora, Aporosa, Aporosella,Argythamnia, Astrococcus, Astrogyne, Baccanrea, Baliospermum, Bernardia,Beyeriopsis, Bischofta, Blachia, Blumeodondron, Bonania, Bradleia,Breynia, Breyniopsis, Briedelia, Buraeavia, Caperonia, Caryodendron,Celianella, Cephalocroton, Chaenotheca, Chaetocarpus, Chamaesyce,Cheilosa, Chiropetalum, Choriophyllum, Cicca, Chaoxylon, Cleidon,Cleistanthus, Cluytia, Cnesmone, Cnidoscolus, Coccoceras, Codiaeum,Coelodiscus, Conami, Conceveiba, Conceveibastrum, Conceveibum, Corythea,Croizatia, Croton, Crotonopsis, Crozophora, Cubanthus, Cunuria,Dactylostemon, Dalechampia, Dendrocousinsia, Diaspersus, Didymocistus,Dimorphocalyx, Discocarpus, Ditaxis, Dodecastingma, Drypetes, Dysopsis,Elateriospermum, Endadenium, Endospermum, Erismanthus, Erythrocarpus,Erythrochilus, Eumecanthus, Euphorbia, Euphorbiodendron, Excoecaria,Flueggea, Calearia, Garcia, Gavarretia, Gelonium, Giara, Givotia,Glochidion, Clochidionopsis, Glycydendron, Gymnanthes, Gymnosparia,Haematospermum, Hendecandra, Hevea, Hieronima, Hieronyma,Hippocrepandra, Homalanthus, Hymenocardia, Janipha, Jatropha,Julocroton, Lasiocroton, Leiocarpus, Leonardia, Lepidanthus,Leucocroton, Mabea, Macaranga, Mallotus, Manihot, Mappa, Maprounea,Melanthesa, Mercurialis, Mettenia, Micrandra, Microdesmis, Microelus,Microstachy, Maocroton, Monadenium, Mozinna, Neoscortechinia,Omalanthus, Omphalea, Ophellantha, Orbicularia, Ostodes, Oxydectes,Palenga, Pantadenia, Paradrypeptes, Pausandra, Pedilanthus, Pera,Peridium, Petalostigma, Phyllanthus, Picrodendro, Pierardia,Pilinophytum, Pimeleodendron, Piranhea, Platygyna, Plukenetia,Podocalyx, Poinsettia, Poraresia, Prosartema, Pseudanthus, Pycnocoma,Quadrasia, Reverchonia, Richeria, Richeriella, Ricinella, Ricinocarpus,Rottlera, Sagotia, Sanwithia, Sapium, Savia, Sclerocroton, Sebastiana,Securinega, Senefeldera, Senefilderopsis, Serophyton, Siphonia,Spathiostemon, Spixia, Stillingia, Strophioblachia, Synadenium,Tetracoccus, Tetraplandra, Tetrorchidium, Thyrsanthera, Tithymalus,Trageia, Trewia, Trigonostemon, Tyria and Xylophylla.
 62. A methodaccording to claim 61 wherein the plant is of the genus Euphorbia.
 63. Amethod according to claim 62 wherein the species of Euphorbia isselected from Euphorbia aaron-rossii, Euphorbia abbreviata, Euphorbiaacuta, Euphorbia alatocaulis, Euphorbia albicaulis, Euphorbiaalgomarginata, Euphorbia aliceae, Euphorbia alta, Euphorbiaanacampseros, Euphorbia andromedae, Euphorbia angusta, Euphorbiaanthonyi, Euphorbia antiguensis, Euphorbia apocynifolia, Euphorbiaarabica, Euphorbia ariensis, Euphorbia arizonica, Euphorbia arkansana,Euphorbia arteagae, Euphorbia arundelana, Euphorbia astroites, Euphorbiaatrococca, Euphorbia baselicis, Euphorbia batabanensis, Euphorbiabergeri, Euphorbia bermudiana, Euphorbia bicolor, Euphorbia biformis,Euphorbia bifurcata, Euphorbia bilobata, Euphorbia biramensis, Euphorbiabiuncialis, Euphorbia blepharostipula, Euphorbia blodgetti, Euphorbiaboerhaavioides, Euphorbia boliviana, Euphorbia bracei, Euphorbiabrachiata, Euphorbia brachycera, Euphorbia brandegee, Euphorbiabrittonii, Euphorbia caesia, Euphorbia calcicola, Euphorbia campestris,Euphorbia candelabrum, Euphorbia capitellata, Euphorbia carmenensis,Euphorbia carunculata, Euphorbia cayensis, Euphorbia celastroides,Euphorbia chalicophila, Euphorbia chamaerrhodos, Euphorbia chamaesula,Euphorbia chiapensis, Euphorbia chiogenoides, Euphorbia cinerascens,Euphorbia clarionensis, Euphorbia colimae, Euphorbia colorata, Euphorbiacommutata, Euphorbia consoquitlae, Euphorbia convolvuloides, Euphorbiacorallifera, Euphorbia creberrima, Euphorbia crenulata, Euphorbiacubensis, Euphorbia cuspidata, Euphorbia cymbiformis, Euphorbiadarlingtonii, Euphorbia defoliata, Euphorbia degeneri, Euphorbiadeltoidea, Euphorbia dentata, Euphorbia depressa Euphorbia dictyosperma,Euphorbia dictyosperma, Euphorbia dioeca, Euphorbia discoidalis,Euphorbia dorsiventralis, Euphorbia drumondii, Euphorbia duclouxii,Euphorbia dussii, Euphorbia eanophylla, Euphorbia eggersii, Euphorbiaeglandulosa, Euphorbia elata, Euphorbia enalla, Euphorbia eriogonoides,Euphorbia eriophylla, Euphorbia esculaeformis, Euphorbia espirituensis,Euphorbia esula, Euphorbia excisa, Euphorbia exclusa, Euphorbiaexstipitata, Euphorbia exstipulata, Euphorbia fendleri, Euphorbiafilicaulis, Euphorbia filiformis, Euphorbia florida, Euphorbiafruticulosa, Euphorbia garber, Euphorbia gaumerii, Euphorbia gerardiana,Euphorbia geyeri, Euphorbia glyptosperma, Euphorbia gorgonis, Euphorbiagracilior, Euphorbia gracillima, Euphorbia gradyi, Euphorbia graminea,Euphorbia graminiea Euphorbia grisea, Euphorbia guadalajarana, Euphorbiaguanarensis, Euphorbia gymnadenia, Euphorbia haematantha, Euphorbiahedyotoides, Euphorbia heldrichii, Euphorbia helenae, Euphorbia helleri,Euphorbia helwigii, Euphorbia henricksonii, Euphorbia heterophylla,Euphorbia hexagona, Euphorbia hexagonoides, Euphorbia hinkleyorum,Euphorbia hintonii, Euphorbia hirtula, Euphorbia hirta, Euphorbiahooveri, Euphorbia humistrata, Euphorbia hypericifolia, Euphorbiainundata, Euphorbia involuta, Euphorbia jaliscensis, Euphorbia jejuna,Euphorbia johnston, Euphorbia juttae, Euphorbia knuthii, Euphorbialasiocarpa, Euphorbia lata, Euphorbia latazi, Euphorbia latericolor,Euphorbia laxiflora Euphorbia lecheoides, Euphorbia ledienii, Euphorbialeucophylla, Euphorbia lineata, Euphorbia linguiformis, Euphorbialongecornuta, Euphorbia longepetiolata, Euphorbia longeramosa, Euphorbialonginsulicola, Euphorbia longipila, Euphorbia lupulina, Euphorbialurida, Euphorbia lycioides, Euphorbia macropodoides, macvaughiana,Euphorbia manca, Euphorbia mandoniana, Euphorbia mangleti, Euphorbiamango, Euphorbia marylandica, Euphorbia mayana, Euphorbia melanadenia,Euphorbia melanocarpa, Euphorbia meridensis, Euphorbia mertonii,Euphorbia mexiae, Euphorbia microcephala, Euphorbia microclada,Euphorbia micromera, Euphorbia misella, Euphorbia missurica, Euphorbiamontana, Euphorbia montereyana, Euphorbia multicaulis, Euphorbiamultiformis, Euphorbia multinodis, Euphorbia multiseta, Euphorbiamuscicola, Euphorbia neomexicana, Euphorbia nephradenia, Euphorbianiqueroana, Euphorbia oaxacana, Euphorbia occidentalis, Euphorbiaodontodenia, Euphorbia olivacea, Euphorbia olowaluana, Euphorbiaopthalmica, Euphorbia ovata, Euphorbia pachypoda, Euphorbia pachyrhiza,Euphorbia padifolia, Euphorbia palmeri, Euphorbia paludicola, Euphorbiaparciflora, Euphorbia parishii, Euphorbia parryi, Euphorbia paxiana,Euphorbia pediculifera, Euphorbia peplidion, Euphorbia peploides,Euphorbia peplus, Euphorbia pergamena, Euphorbia perlignea, Euphorbiapetaloidea, Euphorbia petaloidea, Euphorbia petrina, Euphorbiapicachensis, Euphorbia pilosula, Euphorbia pilulifera, Euphorbiapinariona, Euphorbia pinetorum, Euphorbia pionosperma, Euphorbiaplatysperma, Euphorbia plicata, Euphorbia poeppigii, Euphorbiapoliosperma, Euphorbia polycarpa, Euphorbia polycnemoides, Euphorbiapolyphylla, Euphorbia portoricensis, Euphorbia portulacoides Euphorbiaportulana, Euphorbia preslii, Euphorbia prostrata, Euphorbia pteroneura,Euphorbia pycnanthema, Euphorbia ramosa, Euphorbia rapulum, Euphorbiaremyi, Euphorbia retroscabra, Euphorbia revoluta, Euphorbia rivularis,Euphorbia robusta, Euphorbia romosa, Euphorbia ribida, Euphorbiarubrosperma, Euphorbia rupicola, Euphorbia sanmartensis, Euphorbiasaxatilis M. Bieb, Euphorbia schizoloba, Euphorbia sclerocyathium,Euphorbia scopulorum, Euphorbia senilis, Euphorbia serpyllifolia,Euphorbia serrula, Euphorbia setiloba Engelm, Euphorbia sonorae,Euphorbia soobyi, Euphorbia sparsiflora, Euphorbia sphaerospenna,Euphorbia syphilitica, Euphorbia spruceana, Euphorbia subcoerulea,Euphorbia stellata, Euphorbia submammilaris, Euphorbia subpeltata,Euphorbia subpubens, Euphorbia subreniforme, Euphorbia subtrifoliata,Euphorbia succedanea, Euphorbia tamaulipasana, Euphorbia telephioides,Euphorbia tenuissima, Euphorbia tetrapora, Euphorbia tirucalli,Euphorbia tomentella, Euphorbia tomentosa, Euphorbia torralbasii,Euphorbia tovariensis, Euphorbia trachysperma, Euphorbia tricolor,Euphorbia troyana, Euphorbia tuerckheimii, Euphorbia turczaminowii,Euphorbia umbellulata, Euphorbia undulata, Euphorbia vermiformis,Euphorbia versicolor, Euphorbia villifera, Euphorbia violacea, Euphorbiawhitei, Euphorbia xanti Engelm, Euphorbia xylopoda Greenm., Euphorbiayayalesia Urb., Euphorbia yungasensis, Euphorbia zeravschanica andEuphorbia zinniiflora.
 64. A method according to claim 63 wherein thespecies of Euphorbia is Euphorbia peplus.
 65. A method according toclaim 55 wherein the virus is selected from adenoviruses, papovaviruses,herpesviruses: simplex, varicella-zoster, Epstein-Barr, CMV, poxviruses: smallpox, vaccinia, hepatitis B, rhinoviruses, hepatitis A,poliovirus, rubellavirus, hepatitis C, arboviruses, rabiesvirus,influenzaviruses A and B, measlesvirus, mumpsvirus, HIV, HTLV I and II.66. A method according to claim 65 wherein the virus is HIV, HTLV 1 orHTLV II.
 67. A method according to claim 66 wherein the virus is HIV.68. A method according to claim 65 wherein the virus is Epstein-Barrvirus.
 69. A method according to claim 55 wherein the chemical agent isa jatrophane or a derivative thereof or a pharmaceutically acceptablesalt of these.
 70. A method according to claim 69 wherein saidderivative is an ester derivative.
 71. A method according to claim 69wherein said derivative is an acetylated derivative.
 72. A methodaccording to claim 55 wherein said chemical agent is a pepluane or aderivative thereof or a pharmaceutically acceptable salt of these.
 73. Amethod according to claim 72 wherein said derivative is an esterderivative.
 74. A method according to claim 72 wherein said derivativeis an acetylated derivative.
 75. A method according to claim 55 whereinsaid chemical agent is a paraliane or a derivative thereof or apharmaceutically acceptable salt of these.
 76. A method according toclaim 75 wherein said derivative is an ester derivative.
 77. A methodaccording to claim 75 wherein said derivative is an acetylatedderivative.
 78. A method according to claim 55 wherein said compound isan angeloyl-substituted ingenane or a derivative thereof or apharmaceutically acceptable salt of these.
 79. A method according toclaim 78 wherein said derivative is an acetylated derivative.
 80. Amethod according to claim 78 wherein said jatrophane is of conformation2.
 81. A method according to claim 69 or 72 or 75 or 78 wherein thederivative comprises a substitution as represented in any one of generalformulae (I)-(VI).
 82. A method according to claim 55 wherein saidcompound is 5,8,9,10,14-pentaacetoxy-3-benzoyloxy-15-hydroxypepluane(pepluane) or a derivative thereof or a pharmaceutically acceptable saltof these.
 83. A method according to claim 82 wherein said derivative isan ester derivative.
 84. A method according to claim 55 wherein saidcompound is2,3,5,7,15-pentaacetoxy-9-nicotinoyloxy-14-oxojatropha-6(17),11 E-diene(jatrophane 1) or a derivative thereof or a pharmaceutically acceptablesalt of these.
 85. A method according to claim 84 wherein saidderivative is an ester derivative.
 86. A method according to claim 55wherein said compound is2,5,7,8,9,14-hexaacetoxy-3-benzoyloxy-15-hydroxyjatropha-6(17),11E-diene (jatrophane 2) or a derivative thereof or apharmaceutically acceptable salt of these.
 87. A method according toclaim 86 wherein said derivative is an ester derivative.
 88. A methodaccording to claim 55 wherein said compound is2,5,14-triacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxy-9-nicotinoyloxyjatropha-6(17),11E-diene(jatrophane 3) or a derivative thereof or a pharmaceutically acceptablesalt of these.
 89. A method according to claim 88 wherein saidderivative is an ester derivative.
 90. A method according to claim 55wherein said compound is2,5,9,14-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxyjatropha-6(17),11E-diene)(jatrophane 4) or a derivative thereof or a pharmaceutically acceptablesalt of these.
 91. A method according to claim 90 wherein saidderivative is an ester derivative.
 92. A method according to claim 55wherein said compound is2,5,7,14-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-9-nicotinoyloxyjatropha-6(17),11E-diene(jatrophane 5) or a derivative thereof or a pharmaceutically acceptablesalt of these.
 93. A method according to claim 92 wherein saidderivative is an ester derivative.
 94. A method according to claim 55wherein said compound is2,5,7,9,14-pentaacetoxy-3-benzoyloxy-8,15-dihydroxyjatropha-6(17),11E-diene(jatrophane 6) or a derivative thereof or a pharmaceutically acceptablesalt of these.
 95. A method according to claim 94 wherein saidderivative is an ester derivative.
 96. A method according to claim 55wherein said compound is 20-O-acetyl-ingenol-3-angelate or a derivativethereof or a pharmaceutically acceptable salt of these.
 97. A methodaccording to claim 96 wherein said derivative is an ester derivative.98. A method according to claim 69 or 72 or 75 or 78 or 82 or 84 or 86or 88 or 90 or 92 or 94 or 96 wherein said compound is provided in theform of a composition comprising a pharmaceutically- orcosmetically-acceptable carrier.
 99. A method according to claim 98wherein said carrier is selected from β-alanine betaine hydrochlorideand t-4-hydroxy-N,N-dimethylproline.
 100. Use of a chemical agentor aderivative or chemical analogue thereof as represented by any one of thegeneral formulae (I)-(IV) in the manufacture for the treatment and/orprophylaxis of a condition associated with the presence of a biologicalentity or part thereof or toxin or venom therefrom.
 101. A computerprogram product for assessing the likely usefulness of a candidatecompound or group of compounds for treating or preventing infection orcolonization or presence of a biological entity in a subject, saidproduct comprising: (1) code that receives as input index values for atleast two features associated with said compound(s), wherein saidfeatures are selected from: (a) the ability to modulate PKC activity oreffect; (b) the ability to induce bipolar dendritic activity; (c) theability to be derived from a member of the Euphorbiaceae family; (d) theability to be derived from E. peplus; (e) the ability to be waterextractable from the sap of a Euphorbia species; (f) the ability toactivate latent virus; or (g) less tumor promoting capacity than TPA orPMA. (2) code that adds said index values to provide a sum correspondingto a potency value for said compound(s); and (3) a computer readablemedium that stores the codes.
 102. A computer for assessing the likelyusefulness of a candidate compound or group of compounds for treating orpreventing infection or colonization or presence of a biological entityin a subject, wherein said computer comprises: (1) a machine-readabledata storage medium comprising a data storage material encoded withmachine-readable data, wherein said machine-readable data comprise indexvalues for at least two features associated with said compound(s),wherein said features are selected from: (a) the ability to modulate PKCactivity or effect; (b) the ability to induce bipolar dendriticactivity; (c) the ability to be derived from a member of theEuphorbiaceae family; (d) the ability to be derived from E. peplus; (e)the ability to be water extractable from the sap of a Euphorbia species;(f) the ability to activate latent virus; or (g) less tumor promotingcapacity than TPA or PMA; (2) a working memory for storing instructionsfor processing said machine-readable data; (3) a central-processing unitcoupled to said working memory and to said machine-readable data storagemedium, for processing said machine readable data to provide a sum ofsaid index values corresponding to a potency value for said compound(s);and (4) an output hardware coupled to said central processing unit, forreceiving said potency value.
 103. A process for separating macrocyclicditerpenes from a biomass derived from a Eurphorbiaceace plantcontaining same, said process comprising contacting the biomass with anaqueous solvent for a time and under conditions sufficient to extractthe macrocyclic diterpenes into said solvent and adsorbing themacrocyclic diterpenes to a non-ionic adsorbent.
 104. A processaccording to claim 103 wherein said Euphorbiaceae plant is a species ofthe genus Euphorbia.
 105. A process according to claim 103 or 104wherein the non-ionic adsorbent is a non-ionic porous syntheticadsorbent.
 106. A process according to claim 105 wherein the non-ionicporous synthetic adsorbents is selected from aromatic copolymers mainlycomposed of styrene and divinylbenzene, and methacrylic copolymersmainly composed of monomethacrylate and dimethacrylate.
 107. A processaccording to claim 106 wherein the non-ionic porous synthetic adsorbentsis selected from Amberlite XAD-2, XAD-4, XAD-7, XAD-8 and XAD-16.
 108. Aprocess according to claim 103 or 104 further comprising elutingmacrocyclic diterpenes from the non-ionic adsorbent with water andwater-soluble organic solvent(s).
 109. A process according to claim 108wherein the water-soluble organic solvent(s) are selected from alcohols,ethers, ketones, amides and sulfur-containing compounds.
 110. A processaccording to claim 108 wherein the water-soluble organic solvent ismethanol.
 111. A process according to claim 103 or 104 furthercomprising separating compounds on the basis of molecular size and/orpolarity.
 112. A process according to claim 111 wherein said compoundsare separated using Sephadex HL-20 resin.